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Oxidative Medicine and Cellular Longevity
Volume 2016 (2016), Article ID 1958174, 14 pages
http://dx.doi.org/10.1155/2016/1958174
Review Article

The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance

1Giannina Gaslini Institute, Via Gerolamo Gaslini 5, 16147 Genoa, Italy
2Department of Experimental Medicine, University of Genoa, Via L. B. Alberti 2, 16132 Genoa, Italy
3Bambino Gesù Children’s Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy

Received 24 April 2015; Revised 13 August 2015; Accepted 18 August 2015

Academic Editor: Patrícia Alexandra Madureira

Copyright © 2016 A. L. Furfaro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. C. Gupta, D. Hevia, S. Patchva, B. Park, W. Koh, and B. B. Aggarwal, “Upsides and downsides of reactive oxygen species for Cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy,” Antioxidants and Redox Signaling, vol. 16, no. 11, pp. 1295–1322, 2012. View at Publisher · View at Google Scholar · View at Scopus
  2. T. Ishii, K. Itoh, S. Takahashi et al., “Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages,” Journal of Biological Chemistry, vol. 275, no. 21, pp. 16023–16029, 2000. View at Publisher · View at Google Scholar · View at Scopus
  3. T. Ishii, K. Itoh, E. Ruiz et al., “Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal,” Circulation Research, vol. 94, no. 5, pp. 609–616, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. K. Itoh, J. Mimura, and M. Yamamoto, “Discovery of the negative regulator of Nrf2, keap1: a historical overview,” Antioxidants and Redox Signaling, vol. 13, no. 11, pp. 1665–1678, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. F. Weinberg and N. S. Chandel, “Reactive oxygen species-dependent signaling regulates cancer,” Cellular and Molecular Life Sciences, vol. 66, no. 23, pp. 3663–3673, 2009. View at Publisher · View at Google Scholar · View at Scopus
  6. J. D. Hayes and M. McMahon, “NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer,” Trends in Biochemical Sciences, vol. 34, no. 4, pp. 176–188, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. K. Taguchi, H. Motohashi, and M. Yamamoto, “Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution,” Genes to Cells, vol. 16, no. 2, pp. 123–140, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. N. Traverso, R. Ricciarelli, M. Nitti et al., “Role of glutathione in cancer progression and chemoresistance,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 972913, 10 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. H. Kumar, I.-S. Kim, S. V. More, B.-W. Kim, and D.-K. Choi, “Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases,” Natural Product Reports, vol. 31, no. 1, pp. 109–139, 2014. View at Publisher · View at Google Scholar · View at Scopus
  10. D. Malhotra, E. Portales-Casamar, A. Singh et al., “Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis,” Nucleic Acids Research, vol. 38, no. 17, Article ID gkq212, pp. 5718–5734, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. B. N. Chorley, M. R. Campbell, X. Wang et al., “Identification of novel NRF2-regulated genes by ChiP-Seq: influence on retinoid X receptor alpha,” Nucleic Acids Research, vol. 40, no. 15, pp. 7416–7429, 2012. View at Publisher · View at Google Scholar · View at Scopus
  12. J. D. Hayes and A. T. Dinkova-Kostova, “The Nrf2 regulatory network provides an interface between redox and intermediary metabolism,” Trends in Biochemical Sciences, vol. 39, no. 4, pp. 199–218, 2014. View at Publisher · View at Google Scholar · View at Scopus
  13. P. Moi, K. Chan, I. Asunis, A. Cao, and Y. W. Kan, “Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 21, pp. 9926–9930, 1994. View at Publisher · View at Google Scholar · View at Scopus
  14. M. C. Jaramillo and D. D. Zhang, “The emerging role of the Nrf2-Keap1 signaling pathway in cancer,” Genes and Development, vol. 27, no. 20, pp. 2179–2191, 2013. View at Publisher · View at Google Scholar · View at Scopus
  15. E. J. Moon and A. Giaccia, “Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment,” Free Radical Biology and Medicine, vol. 79, pp. 292–299, 2015. View at Publisher · View at Google Scholar · View at Scopus
  16. Y. Hirotsu, F. Katsuoka, R. Funayama et al., “Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks,” Nucleic Acids Research, vol. 40, no. 20, pp. 10228–10239, 2012. View at Publisher · View at Google Scholar · View at Scopus
  17. K. I. Tong, Y. Katoh, H. Kusunoki, K. Itoh, T. Tanaka, and M. Yamamoto, “Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model,” Molecular and Cellular Biology, vol. 26, no. 8, pp. 2887–2900, 2006. View at Publisher · View at Google Scholar · View at Scopus
  18. J.-H. Kim, S. Yu, J. D. Chen, and A. N. Kong, “The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains,” Oncogene, vol. 32, no. 4, pp. 514–527, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. P. Rada, A. I. Rojo, S. Chowdhry, M. McMahon, J. D. Hayes, and A. Cuadrado, “SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner,” Molecular and Cellular Biology, vol. 31, no. 6, pp. 1121–1133, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. H. Wang, K. Liu, M. Geng et al., “RXRα inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2,” Cancer Research, vol. 73, no. 10, pp. 3097–3108, 2013. View at Publisher · View at Google Scholar · View at Scopus
  21. S. B. Cullinan, J. D. Gordan, J. Jin, J. W. Harper, and J. A. Diehl, “The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase,” Molecular and Cellular Biology, vol. 24, no. 19, pp. 8477–8486, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. A. Kobayashi, M.-I. Kang, H. Okawa et al., “Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2,” Molecular and Cellular Biology, vol. 24, no. 16, pp. 7130–7139, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. A. Kobayashi, M.-I. Kang, Y. Watai et al., “Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1,” Molecular and Cellular Biology, vol. 26, no. 1, pp. 221–229, 2006. View at Publisher · View at Google Scholar · View at Scopus
  24. W. O. Osburn and T. W. Kensler, “Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults,” Mutation Research—Reviews in Mutation Research, vol. 659, no. 1-2, pp. 31–39, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. K. Itoh, N. Wakabayashi, Y. Katoh et al., “Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain,” Genes & Development, vol. 13, no. 1, pp. 76–86, 1999. View at Publisher · View at Google Scholar · View at Scopus
  26. R. Holland and J. C. Fishbein, “Chemistry of the cysteine sensors in kelch-like ECH-associated protein 1,” Antioxidants and Redox Signaling, vol. 13, no. 11, pp. 1749–1761, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. T. Yamamoto, T. Suzuki, A. Kobayashi et al., “Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity,” Molecular and Cellular Biology, vol. 28, no. 8, pp. 2758–2770, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. A. T. Dinkova-Kostova, W. D. Holtzclaw, R. N. Cole et al., “Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 18, pp. 11908–11913, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. N. Wakabayashi, A. T. Dinkova-Kostova, W. D. Holtzclaw et al., “Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 7, pp. 2040–2045, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. K. Takaya, T. Suzuki, H. Motohashi et al., “Validation of the multiple sensor mechanism of the Keap1-Nrf2 system,” Free Radical Biology and Medicine, vol. 53, no. 4, pp. 817–827, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. H. K. Bryan, A. Olayanju, C. E. Goldring, and B. K. Park, “The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation,” Biochemical Pharmacology, vol. 85, no. 6, pp. 705–717, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Kobayashi, L. Li, N. Iwamoto et al., “The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds,” Molecular and Cellular Biology, vol. 29, no. 2, pp. 493–502, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. M. Komatsu, H. Kurokawa, S. Waguri et al., “The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1,” Nature Cell Biology, vol. 12, no. 3, pp. 213–223, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. Y. Ichimura, S. Waguri, Y.-S. Sou et al., “Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy,” Molecular Cell, vol. 51, no. 5, pp. 618–631, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. K. Taguchi, N. Fujikawa, M. Komatsu et al., “Keap1 degradation by autophagy for the maintenance of redox homeostasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 34, pp. 13561–13566, 2012. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Wu, F. Zhao, B. Gao et al., “Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis,” Genes and Development, vol. 28, no. 7, pp. 708–722, 2014. View at Publisher · View at Google Scholar · View at Scopus
  37. S. Chowdhry, Y. Zhang, M. McMahon, C. Sutherland, A. Cuadrado, and J. D. Hayes, “Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity,” Oncogene, vol. 32, no. 32, pp. 3765–3781, 2013. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Tao, S. Wang, S. J. Moghaddam et al., “Oncogenic KRAS confers chemoresistance by upregulating NRF2,” Cancer Research, vol. 74, no. 24, pp. 7430–7441, 2014. View at Publisher · View at Google Scholar · View at Scopus
  39. G. M. Denicola, F. A. Karreth, T. J. Humpton et al., “Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis,” Nature, vol. 475, no. 7354, pp. 106–109, 2011. View at Publisher · View at Google Scholar · View at Scopus
  40. M. Ramos-Gomez, M.-K. Kwak, P. M. Dolan et al., “Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 6, pp. 3410–3415, 2001. View at Publisher · View at Google Scholar · View at Scopus
  41. K. Iida, K. Itoh, Y. Kumagai et al., “Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis,” Cancer Research, vol. 64, no. 18, pp. 6424–6431, 2004. View at Publisher · View at Google Scholar · View at Scopus
  42. C. Xu, M.-T. Huang, G. Shen et al., “Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2,” Cancer Research, vol. 66, no. 16, pp. 8293–8296, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. T. O. Khor, M.-T. Huang, A. Prawan et al., “Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer,” Cancer Prevention Research, vol. 1, no. 3, pp. 187–191, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. L. Becks, M. Prince, H. Burson et al., “Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene,” BMC Cancer, vol. 10, article 540, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. T. Yamamoto, K. Yoh, A. Kobayashi et al., “Identification of polymorphisms in the promoter region of the human NRF2 gene,” Biochemical and Biophysical Research Communications, vol. 321, no. 1, pp. 72–79, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. T. Suzuki, T. Shibata, K. Takaya et al., “Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels,” Molecular and Cellular Biology, vol. 33, no. 12, pp. 2402–2412, 2013. View at Publisher · View at Google Scholar · View at Scopus
  47. X.-J. Wang, Z. Sun, N. F. Villeneuve et al., “Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2,” Carcinogenesis, vol. 29, no. 6, pp. 1235–1243, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. H.-K. Na and Y.-J. Surh, “Oncogenic potential of Nrf2 and its principal target protein heme oxygenase-1,” Free Radical Biology and Medicine, vol. 67, pp. 353–365, 2014. View at Publisher · View at Google Scholar · View at Scopus
  49. T. Shibata, T. Ohta, K. I. Tong et al., “Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 36, pp. 13568–13573, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. D. D. Zhang, “Mechanistic studies of the Nrf2-Keap1 signaling pathway,” Drug Metabolism Reviews, vol. 38, no. 4, pp. 769–789, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. P. Nioi and T. Nguyen, “A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity,” Biochemical and Biophysical Research Communications, vol. 362, no. 4, pp. 816–821, 2007. View at Publisher · View at Google Scholar · View at Scopus
  52. D. R. Stacy, K. Ely, P. P. Massion et al., “Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas,” Head and Neck, vol. 28, no. 9, pp. 813–818, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. M. G. P. van der Wijst, R. Brown, and M. G. Rots, “Nrf2, the master redox switch: the Achilles' heel of ovarian cancer?” Biochimica et Biophysica Acta—Reviews on Cancer, vol. 1846, no. 2, pp. 494–509, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. T. Jiang, N. Chen, F. Zhao et al., “High levels of Nrf2 determine chemoresistance in type II endometrial cancer,” Cancer Research, vol. 70, no. 13, pp. 5486–5496, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. Mitsuishi, H. Motohashi, and M. Yamamoto, “The Keap1–Nrf2 system in cancers: stress response and anabolic metabolism,” Frontiers in Oncology, vol. 2, article 200, 2012. View at Publisher · View at Google Scholar
  56. T. Shibata, S. Saito, A. Kokubu, T. Suzuki, M. Yamamoto, and S. Hirohashi, “Global downstream pathway analysis reveals a dependence of oncogenic NF—E2-related factor 2 mutation on the mTOR growth signaling pathway,” Cancer Research, vol. 70, no. 22, pp. 9095–9105, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. P. Shelton and A. K. Jaiswal, “The transcription factor NF-E2-related factor 2 (nrf2): a protooncogene?” The FASEB Journal, vol. 27, no. 2, pp. 414–423, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. L. A. Muscarella, P. Parrella, V. D'Alessandro et al., “Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer,” Epigenetics, vol. 6, no. 6, pp. 710–719, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. P. Zhang, A. Singh, S. Yegnasubramanian et al., “Loss of kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth,” Molecular Cancer Therapeutics, vol. 9, no. 2, pp. 336–346, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. N. Hanada, T. Takahata, Q. Zhou et al., “Methylation of the KEAP1 gene promoter region in human colorectal cancer,” BMC Cancer, vol. 12, article 66, 2012. View at Publisher · View at Google Scholar · View at Scopus
  61. A. Ooi, K. Dykema, A. Ansari et al., “CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma,” Cancer Research, vol. 73, no. 7, pp. 2044–2051, 2013. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Loignon, W. Miao, L. Hu et al., “Cul3 overexpression depletes Nrf2 in breast cancer and is associated with sensitivity to carcinogens, to oxidative stress, and to chemotherapy,” Molecular Cancer Therapeutics, vol. 8, no. 8, pp. 2432–2440, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. V. D. Martinez, E. A. Vucic, K. L. Thu, L. A. Pikor, S. Lam, and W. L. Lam, “Disruption of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex components by multiple genetic mechanisms: association with poor prognosis in head and neck cancer,” Head and Neck, vol. 37, no. 5, pp. 727–734, 2015. View at Publisher · View at Google Scholar · View at Scopus
  64. V. D. Martinez, E. A. Vucic, K. L. Thu, L. A. Pikor, R. Hubaux, and W. L. Lam, “Unique pattern of component gene disruption in the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in serous ovarian cancer,” BioMed Research International, vol. 2014, Article ID 159459, 10 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  65. V. D. Martinez, E. A. Vucic, L. A. Pikor, K. L. Thu, R. Hubaux, and W. L. Lam, “Frequent concerted genetic mechanisms disrupt multiple components of the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in thyroid cancer,” Molecular Cancer, vol. 12, no. 1, article 124, 2013. View at Publisher · View at Google Scholar · View at Scopus
  66. N. F. Villeneuve, Z. Sun, W. Chen, and D. D. Zhang, “Nrf2 and p21 regulate the fine balance between life and death by controlling ROS levels,” Cell Cycle, vol. 8, no. 20, pp. 3255–3256, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. W. Chen, Z. Sun, X.-J. Wang et al., “Direct interaction between Nrf2 and p21Cip1/WAF1 upregulates the Nrf2-mediated antioxidant response,” Molecular Cell, vol. 34, no. 6, pp. 663–673, 2009. View at Publisher · View at Google Scholar
  68. C. M. Clements, R. S. McNally, B. J. Conti, T. W. Mak, and J. P.-Y. Ting, “DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 41, pp. 15091–15096, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. L. Gan, D. A. Johnson, and J. A. Johnson, “Keap1-Nrf2 activation in the presence and absence of DJ-1,” European Journal of Neuroscience, vol. 31, no. 6, pp. 967–977, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. J. P. MacKeigan, C. M. Clements, J. D. Lich, R. M. Pope, Y. Hod, and J. P.-Y. Ting, “Proteomic profiling drug-induced apoptosis in non-small cell lung carcinoma: identification of RS/DJ-1 and RhoGDIalpha,” Cancer Research, vol. 63, no. 20, pp. 6928–6934, 2003. View at Google Scholar · View at Scopus
  71. T. Taira, Y. Saito, T. Niki, S. M. M. Iguchi-Ariga, K. Takahashi, and H. Ariga, “DJ-1 has a role in antioxidative stress to prevent cell death,” The EMBO Reports, vol. 5, no. 2, pp. 213–218, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. I. M. Copple, A. Lister, A. D. Obeng et al., “Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway,” The Journal of Biological Chemistry, vol. 285, no. 22, pp. 16782–16788, 2010. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Jain, T. Lamark, E. Sjøttem et al., “p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription,” Journal of Biological Chemistry, vol. 285, no. 29, pp. 22576–22591, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. N. D. Camp, R. G. James, D. W. Dawson et al., “Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein,” Journal of Biological Chemistry, vol. 287, no. 9, pp. 6539–6550, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. J. Ma, H. Cai, T. Wu et al., “PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function,” Molecular and Cellular Biology, vol. 32, no. 8, pp. 1506–1517, 2012. View at Publisher · View at Google Scholar · View at Scopus
  76. B. E. Hast, D. Goldfarb, K. M. Mulvaney et al., “Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination,” Cancer Research, vol. 73, no. 7, pp. 2199–2210, 2013. View at Publisher · View at Google Scholar · View at Scopus
  77. N. Wakabayashi, S. Shin, S. L. Slocum et al., “Regulation of Notch1 signaling by Nrf2: implications for tissue regeneration,” Science Signaling, vol. 3, no. 130, article ra52, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. A. You, C.-W. Nam, N. Wakabayashi, M. Yamamoto, T. W. Kensler, and M.-K. Kwak, “Transcription factor Nrf2 maintains the basal expression of Mdm2: an implication of the regulation of p53 signaling by Nrf2,” Archives of Biochemistry and Biophysics, vol. 507, no. 2, pp. 356–364, 2011. View at Publisher · View at Google Scholar · View at Scopus
  79. J. Wang, M. Zhang, L. Zhang et al., “Correlation of Nrf2, HO-1, and MRP3 in gallbladder cancer and their relationships to clinicopathologic features and survival,” Journal of Surgical Research, vol. 164, no. 1, pp. e99–e105, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. W. D. Kim, Y. W. Kim, I. J. Cho, C. H. Lee, and S. G. Kim, “E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells,” Journal of Cell Science, vol. 125, no. 5, pp. 1284–1295, 2012. View at Publisher · View at Google Scholar · View at Scopus
  81. A. K. Jain, D. A. Bloom, and A. K. Jaiswal, “Nuclear import and export signals in control of Nrf2,” The Journal of Biological Chemistry, vol. 280, no. 32, pp. 29158–29168, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. H. Shen, Y. Yang, S. Xia, B. Rao, J. Zhang, and J. Wang, “Blockage of Nrf2 suppresses the migration and invasion of esophageal squamous cell carcinoma cells in hypoxic microenvironment,” Diseases of the Esophagus, vol. 27, no. 7, pp. 685–692, 2014. View at Publisher · View at Google Scholar · View at Scopus
  83. G. L. Semenza, “Intratumoral hypoxia, radiation resistance, and HIF-1,” Cancer Cell, vol. 5, no. 5, pp. 405–406, 2004. View at Publisher · View at Google Scholar · View at Scopus
  84. T.-H. Kim, E.-G. Hur, S.-J. Kang et al., “NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1α,” Cancer Research, vol. 71, no. 6, pp. 2260–2275, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. G.-S. Shim, S. Manandhar, D.-H. Shin, T.-H. Kim, and M.-K. Kwak, “Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway,” Free Radical Biology and Medicine, vol. 47, no. 11, pp. 1619–1631, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. Y. Zhong, F. Zhang, Z. Sun et al., “Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response,” Molecular Carcinogenesis, vol. 52, no. 10, pp. 824–834, 2013. View at Publisher · View at Google Scholar · View at Scopus
  87. S. Homma, Y. Ishii, Y. Morishima et al., “Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer,” Clinical Cancer Research, vol. 15, no. 10, pp. 3423–3432, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. S. Jayakumar, A. Kunwar, S. K. Sandur, B. N. Pandey, and R. C. Chaubey, “Differential response of DU145 and PC3 prostate cancer cells to ionizing radiation: role of reactive oxygen species, GSH and Nrf2 in radiosensitivity,” Biochimica et Biophysica Acta—General Subjects, vol. 1840, no. 1, pp. 485–494, 2014. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Lee, M.-J. Lim, M.-H. Kim et al., “An effective strategy for increasing the radiosensitivity of Human lung Cancer cells by blocking Nrf2-dependent antioxidant responses,” Free Radical Biology and Medicine, vol. 53, no. 4, pp. 807–816, 2012. View at Publisher · View at Google Scholar · View at Scopus
  90. A. L. Furfaro, J. R. Z. MacAy, B. Marengo et al., “Resistance of neuroblastoma GI-ME-N cell line to glutathione depletion involves Nrf2 and heme oxygenase-1,” Free Radical Biology and Medicine, vol. 52, no. 2, pp. 488–496, 2012. View at Publisher · View at Google Scholar · View at Scopus
  91. A. L. Furfaro, S. Piras, M. Passalacqua et al., “HO-1 up-regulation: a key point in high-risk neuroblastoma resistance to bortezomib,” Biochimica et Biophysica Acta, vol. 1842, no. 4, pp. 613–622, 2014. View at Publisher · View at Google Scholar · View at Scopus
  92. A. Singh, H. Wu, P. Zhang, C. Happel, J. Ma, and S. Biswal, “Expression of ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers side population and chemoresistance phenotype,” Molecular Cancer Therapeutics, vol. 9, no. 8, pp. 2365–2376, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. C. Geismann, A. Arlt, S. Sebens, and H. Schäfer, “Cytoprotection “gone astray”: Nrf2 and its role in cancer,” OncoTargets and Therapy, vol. 7, pp. 1497–1518, 2014. View at Publisher · View at Google Scholar · View at Scopus
  94. C. M. Mahaffey, H. Zhang, A. Rinna, W. Holland, P. C. Mack, and H. J. Forman, “Multidrug-resistant protein-3 gene regulation by the transcription factor Nrf2 in human bronchial epithelial and non-small-cell lung carcinoma,” Free Radical Biology and Medicine, vol. 46, no. 12, pp. 1650–1657, 2009. View at Publisher · View at Google Scholar · View at Scopus
  95. S. L. Slocum and T. W. Kensler, “Nrf2: control of sensitivity to carcinogens,” Archives of Toxicology, vol. 85, no. 4, pp. 273–284, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. J. J. Tsai, J. A. Dudakov, K. Takahashi et al., “Nrf2 regulates haematopoietic stem cell function,” Nature Cell Biology, vol. 15, no. 3, pp. 309–316, 2013. View at Publisher · View at Google Scholar · View at Scopus
  97. D. M. Santos, M. M. M. Santos, R. Moreira, S. Solá, and C. M. P. Rodrigues, “Synthetic condensed 1,4-naphthoquinone derivative shifts neural stem cell differentiation by regulating redox state,” Molecular Neurobiology, vol. 47, no. 1, pp. 313–324, 2013. View at Publisher · View at Google Scholar · View at Scopus
  98. S. Murakami and H. Motohashi, “Roles of NRF2 in cell proliferation and differentiation,” Free Radical Biology and Medicine, 2015. View at Publisher · View at Google Scholar
  99. T.-C. A. Johannessen, R. Bjerkvig, and B. B. Tysnes, “DNA repair and cancer stem-like cells—potential partners in glioma drug resistance?” Cancer Treatment Reviews, vol. 34, no. 6, pp. 558–567, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. J. Zhu, H. Wang, Q. Sun et al., “Nrf2 is required to maintain the self-renewal of glioma stem cells,” BMC Cancer, vol. 13, article 380, 2013. View at Publisher · View at Google Scholar · View at Scopus
  101. J. Zhu, H. Wang, X. Ji et al., “Differential Nrf2 expression between glioma stem cells and non-stem-like cells in glioblastoma,” Oncology Letters, vol. 7, no. 3, pp. 693–698, 2014. View at Publisher · View at Google Scholar · View at Scopus
  102. T. Wu, B. G. Harder, P. K. Wong, J. E. Lang, and D. D. Zhang, “Oxidative stress, mammospheres and Nrf2-new implication for breast cancer therapy?” Molecular Carcinogenesis, 2014. View at Publisher · View at Google Scholar
  103. G. M. Trakshel and M. D. Maines, “Multiplicity of heme oxygenase isozymes. HO-1 and HO-2 are different molecular species in rat and rabbit,” Journal of Biological Chemistry, vol. 264, no. 2, pp. 1323–1328, 1989. View at Google Scholar · View at Scopus
  104. M. D. Maines, “Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications,” The FASEB Journal, vol. 2, no. 10, pp. 2557–2568, 1988. View at Google Scholar · View at Scopus
  105. S. W. Ryter and A. M. K. Choi, “Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation,” Translational Research, 2015. View at Publisher · View at Google Scholar
  106. M. D. Maines, G. M. Trakshel, and R. K. Kutty, “Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible,” The Journal of Biological Chemistry, vol. 261, no. 1, pp. 411–419, 1986. View at Google Scholar · View at Scopus
  107. J. Alam, S. Shibahara, and A. Smith, “Transcriptional activation of the heme oxygenase gene by heme and cadmium in mouse hepatoma cells,” Journal of Biological Chemistry, vol. 264, no. 11, pp. 6371–6375, 1989. View at Google Scholar · View at Scopus
  108. S. M. Keyse and R. M. Tyrrell, “Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 1, pp. 99–103, 1989. View at Publisher · View at Google Scholar · View at Scopus
  109. R. Foresti, J. E. Clark, C. J. Green, and R. Motterlini, “Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells: involvement of superoxide and peroxynitrite anions,” The Journal of Biological Chemistry, vol. 272, no. 29, pp. 18411–18417, 1997. View at Publisher · View at Google Scholar · View at Scopus
  110. C. M. Terry, J. A. Clikeman, J. R. Hoidal, and K. S. Callahan, “Effect of tumor necrosis factor-alpha and interleukin-1α on heme oxygenase-1 expression in human endothelial cells,” American Journal of Physiology, vol. 274, no. 3, part 2, pp. H883–H891, 1998. View at Google Scholar
  111. R. Stocker, Y. Yamamoto, A. F. McDonagh, A. N. Glazer, and B. N. Ames, “Bilirubin is an antioxidant of possible physiological importance,” Science, vol. 235, no. 4792, pp. 1043–1046, 1987. View at Publisher · View at Google Scholar · View at Scopus
  112. S. Brouard, L. E. Otterbein, J. Anrather et al., “Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis,” Journal of Experimental Medicine, vol. 192, no. 7, pp. 1015–1026, 2000. View at Publisher · View at Google Scholar · View at Scopus
  113. R. J. Ward, S. Wilmet, R. Legssyer, and R. R. Crichton, “The influence of iron homoeostasis on macrophage function,” Biochemical Society Transactions, vol. 30, no. 4, pp. 762–765, 2002. View at Publisher · View at Google Scholar · View at Scopus
  114. S. W. Ryter and A. M. K. Choi, “Heme oxygenase-1: redox regulation of a stress protein in lung and cell culture models,” Antioxidants and Redox Signaling, vol. 7, no. 1-2, pp. 80–91, 2005. View at Publisher · View at Google Scholar · View at Scopus
  115. A. Prawan, J. K. Kundu, and Y.-J. Surh, “Molecular basis of heme oxygenase-1 induction: implications for chemoprevention and chemoprotection,” Antioxidants and Redox Signaling, vol. 7, no. 11-12, pp. 1688–1703, 2005. View at Publisher · View at Google Scholar · View at Scopus
  116. A. Jozkowicz, H. Was, and J. Dulak, “Heme oxygenase-1 in tumors: Is it a false friend?” Antioxidants and Redox Signaling, vol. 9, no. 12, pp. 2099–2117, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. P. Banerjee, A. Basu, D. Datta, M. Gasser, A. M. Waaga-Gasser, and S. Pal, “The heme oxygenase-1 protein is overexpressed in human renal cancer cells following activation of the Ras-Raf-ERK pathway and mediates anti-apoptotic signal,” The Journal of Biological Chemistry, vol. 286, no. 38, pp. 33580–33590, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. H. Yin, J. Fang, L. Liao, H. Maeda, and Q. Su, “Upregulation of heme oxygenase-1 in colorectal cancer patients with increased circulation carbon monoxide levels, potentially affects chemotherapeutic sensitivity,” BMC Cancer, vol. 14, no. 1, article 436, 2014. View at Publisher · View at Google Scholar · View at Scopus
  119. P. O. Berberat, Z. Dambrauskas, A. Gulbinas et al., “Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment,” Clinical Cancer Research, vol. 11, no. 10, pp. 3790–3798, 2005. View at Publisher · View at Google Scholar · View at Scopus
  120. M. S. Degese, J. E. Mendizabal, N. A. Gandini et al., “Expression of heme oxygenase-1 in non-small cell lung cancer (NSCLC) and its correlation with clinical data,” Lung Cancer, vol. 77, no. 1, pp. 168–175, 2012. View at Publisher · View at Google Scholar · View at Scopus
  121. M. Miyake, K. Fujimoto, S. Anai et al., “Clinical significance of heme oxygenase-1 expression in non-muscle-invasive bladder cancer,” Urologia Internationalis, vol. 85, no. 3, pp. 355–363, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. J.-R. Tsai, H.-M. Wang, P.-L. Liu et al., “High expression of heme oxygenase-1 is associated with tumor invasiveness and poor clinical outcome in non-small cell lung cancer patients,” Cellular Oncology, vol. 35, no. 6, pp. 461–471, 2012. View at Publisher · View at Google Scholar · View at Scopus
  123. H. Was, T. Cichon, R. Smolarczyk et al., “Overexpression of heme oxygenase-1 in murine melanoma: increased proliferation and viability of tumor cells, decreased survival of mice,” The American Journal of Pathology, vol. 169, no. 6, pp. 2181–2198, 2006. View at Publisher · View at Google Scholar · View at Scopus
  124. M. Sunamura, D. G. Duda, M. H. Ghattas et al., “Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer,” Angiogenesis, vol. 6, no. 1, pp. 15–24, 2003. View at Publisher · View at Google Scholar · View at Scopus
  125. S.-S. Lee, S.-F. Yang, C.-H. Tsai, M.-C. Chou, M.-Y. Chou, and Y.-C. Chang, “Upregulation of heme oxygenase-1 expression in areca-quid-chewing-associated oral squamous cell carcinoma,” Journal of the Formosan Medical Association, vol. 107, no. 5, pp. 355–363, 2008. View at Publisher · View at Google Scholar · View at Scopus
  126. M. A. Alaoui-Jamali, T. A. Bismar, A. Gupta et al., “A novel experimental heme oxygenase-1-targeted therapy for hormone-refractory prostate cancer,” Cancer Research, vol. 69, no. 20, pp. 8017–8024, 2009. View at Publisher · View at Google Scholar · View at Scopus
  127. G. Sass, P. Leukel, V. Schmitz et al., “Inhibition of heme oxygenase 1 expression by small interfering RNA decreases orthotopic tumor growth in livers of mice,” International Journal of Cancer, vol. 123, no. 6, pp. 1269–1277, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. M. J. Marinissen, T. Tanos, M. Bolós, M. R. De Sagarra, O. A. Coso, and A. Cuadrado, “Inhibition of heme oxygenase-1 interferes with the transforming activity of the Kaposi sarcoma herpesvirus-encoded G protein-coupled receptor,” The Journal of Biological Chemistry, vol. 281, no. 16, pp. 11332–11346, 2006. View at Publisher · View at Google Scholar · View at Scopus
  129. H. Was, J. Dulak, and A. Jozkowicz, “Heme oxygenase-1 in tumor biology and therapy,” Current Drug Targets, vol. 11, no. 12, pp. 1551–1570, 2010. View at Publisher · View at Google Scholar · View at Scopus
  130. A. Loboda, A. Jazwa, A. Grochot-Przeczek et al., “Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities,” Antioxidants & Redox Signaling, vol. 10, no. 10, pp. 1767–1812, 2008. View at Publisher · View at Google Scholar · View at Scopus
  131. J. Fang, K. Greish, H. Qin et al., “HSP32 (HO-1) inhibitor, copoly(styrene-maleic acid)-zinc protoporphyrin IX, a water-soluble micelle as anticancer agent: in vitro and in vivo anticancer effect,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 81, no. 3, pp. 540–547, 2012. View at Publisher · View at Google Scholar · View at Scopus
  132. H. Nakamura, L. Liao, Y. Hitaka et al., “Micelles of zinc protoporphyrin conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer for imaging and light-induced antitumor effects in vivo,” Journal of Controlled Release, vol. 165, no. 3, pp. 191–198, 2013. View at Publisher · View at Google Scholar · View at Scopus
  133. P. Nuhn, B. M. Künzli, R. Hennig et al., “Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo,” Molecular Cancer, vol. 8, article 37, 2009. View at Publisher · View at Google Scholar · View at Scopus
  134. W. Zhang, T. Qiao, and L. Zha, “Inhibition of heme oxygenase-1 enhances the radiosensitivity in human nonsmall cell lung cancer A549 cells,” Cancer Biotherapy and Radiopharmaceuticals, vol. 26, no. 5, pp. 639–645, 2011. View at Publisher · View at Google Scholar · View at Scopus
  135. D. Nowis, M. Legat, T. Grzela et al., “Heme oxygenase-1 protects tumor cells against photodynamic therapy-mediated cytotoxicity,” Oncogene, vol. 25, no. 24, pp. 3365–3374, 2006. View at Publisher · View at Google Scholar · View at Scopus
  136. D. Ma, Q. Fang, P. Wang et al., “Induction of heme oxygenase-1 by Na+-H+ exchanger 1 protein plays a crucial role in imatinib-resistant chronic myeloid leukemia cells,” The Journal of Biological Chemistry, vol. 290, no. 20, pp. 12558–12571, 2015. View at Publisher · View at Google Scholar
  137. W.-K. Jeon, H.-Y. Hong, W.-C. Seo et al., “Smad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition,” Biochemical and Biophysical Research Communications, vol. 420, no. 2, pp. 288–292, 2012. View at Publisher · View at Google Scholar · View at Scopus
  138. Y. Yin, Q. Liu, B. Wang, G. Chen, L. Xu, and H. Zhou, “Expression and function of heme oxygenase-1 in human gastric cancer,” Experimental Biology and Medicine, vol. 237, no. 4, pp. 362–371, 2012. View at Publisher · View at Google Scholar · View at Scopus
  139. M. Mayerhofer, S. Florian, M.-T. Krauth et al., “Identification of heme oxygenase-1 as a novel BCR/ABL-dependent survival factor in chronic myeloid leukemia,” Cancer Research, vol. 64, no. 9, pp. 3148–3154, 2004. View at Publisher · View at Google Scholar · View at Scopus
  140. M. Hill, V. Pereira, C. Chauveau et al., “Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase,” The FASEB Journal, vol. 19, no. 14, pp. 1957–1968, 2005. View at Publisher · View at Google Scholar · View at Scopus
  141. M. Ferrando, G. Gueron, B. Elguero et al., “Heme oxygenase 1 (HO-1) challenges the angiogenic switch in prostate cancer,” Angiogenesis, vol. 14, no. 4, pp. 467–479, 2011. View at Publisher · View at Google Scholar · View at Scopus
  142. C.-Y. Chao, C.-K. Lii, Y.-T. Hsu et al., “Induction of heme oxygenase-1 and inhibition of TPA-induced matrix metalloproteinase-9 expression by andrographolide in MCF-7 human breast cancer cells,” Carcinogenesis, vol. 34, no. 8, pp. 1843–1851, 2013. View at Publisher · View at Google Scholar · View at Scopus
  143. B. Wegiel, Z. Nemeth, M. Correa-Costa, A. C. Bulmer, and L. E. Otterbein, “Heme oxygenase-1: a metabolic nike,” Antioxidants and Redox Signaling, vol. 20, no. 11, pp. 1709–1722, 2014. View at Publisher · View at Google Scholar · View at Scopus
  144. S. W. Ryter, S. Xi, C. L. Hartsfield, and A. M. K. Choi, “Mitogen activated protein kinase (MAPK) pathway regulates heme oxygenase-1 gene expression by hypoxia in vascular cells,” Antioxidants and Redox Signaling, vol. 4, no. 4, pp. 587–592, 2002. View at Publisher · View at Google Scholar · View at Scopus
  145. C.-C. Lin, L.-L. Chiang, C.-H. Lin et al., “Transforming growth factor-beta1 stimulates heme oxygenase-1 expression via the PI3K/Akt and NF-kappaB pathways in human lung epithelial cells,” European Journal of Pharmacology, vol. 560, no. 2-3, pp. 101–109, 2007. View at Publisher · View at Google Scholar · View at Scopus
  146. Y. Lavrovsky, M. L. Schwartzman, R. D. Levere, A. Kappas, and N. G. Abraham, “Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 13, pp. 5987–5991, 1994. View at Publisher · View at Google Scholar · View at Scopus
  147. S. A. Rushworth, K. M. Bowles, P. Raninga, and D. J. MacEwan, “NF-κB-Lnhibited acute myeloid leukemia cells are rescued from apoptosis by heme oxygenase-1 induction,” Cancer Research, vol. 70, no. 7, pp. 2973–2983, 2010. View at Publisher · View at Google Scholar · View at Scopus
  148. E. O. Farombi and Y.-J. Surh, “Heme oxygenase-1 as a potential therapeutic target for hepatoprotection,” Journal of Biochemistry and Molecular Biology, vol. 39, no. 5, pp. 479–491, 2006. View at Publisher · View at Google Scholar · View at Scopus
  149. L.-H. Wang, Y. Li, S.-N. Yang et al., “Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling,” British Journal of Cancer, vol. 110, no. 2, pp. 341–352, 2014. View at Publisher · View at Google Scholar · View at Scopus
  150. S. Nemmiche, D. Chabane-Sari, M. Kadri, and P. Guiraud, “Cadmium-induced apoptosis in the BJAB human B cell line: involvement of PKC/ERK1/2/JNK signaling pathways in HO-1 expression,” Toxicology, vol. 300, no. 3, pp. 103–111, 2012. View at Publisher · View at Google Scholar · View at Scopus
  151. P.-Y. Cheng, Y.-M. Lee, N.-L. Shih, Y.-C. Chen, and M.-H. Yen, “Heme oxygenase-1 contributes to the cytoprotection of alpha-lipoic acid via activation of p44/42 mitogen-activated protein kinase in vascular smooth muscle cells,” Free Radical Biology and Medicine, vol. 40, no. 8, pp. 1313–1322, 2006. View at Publisher · View at Google Scholar · View at Scopus
  152. M. T. Do, H. G. Kim, T. Khanal et al., “Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways,” Toxicology and Applied Pharmacology, vol. 271, no. 2, pp. 229–238, 2013. View at Publisher · View at Google Scholar · View at Scopus
  153. L. N. Barrera, S. A. Rushworth, K. M. Bowles, and D. J. MacEwan, “Bortezomib induces heme oxygenase-1 expression in multiple myeloma,” Cell Cycle, vol. 11, no. 12, pp. 2248–2252, 2012. View at Publisher · View at Google Scholar · View at Scopus
  154. S. Bancos, C. J. Baglole, I. Rahman, and R. P. Phipps, “Induction of heme oxygenase-1 in normal and malignant B lymphocytes by 15-deoxy-12.14-prostaglandin J2 requires Nrf2,” Cellular Immunology, vol. 262, no. 1, pp. 18–27, 2010. View at Publisher · View at Google Scholar · View at Scopus
  155. D.-Y. Lu, W.-L. Yeh, S.-M. Huang, C.-H. Tang, H.-Y. Lin, and S.-J. Chou, “Osteopontin increases heme oxygenase-1 expression and subsequently induces cell migration and invasion in glioma cells,” Neuro-Oncology, vol. 14, no. 11, pp. 1367–1378, 2012. View at Publisher · View at Google Scholar · View at Scopus
  156. L.-J. Bao, M. C. Jaramillo, Z.-B. Zhang et al., “Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma,” International Journal of Clinical and Experimental Pathology, vol. 7, no. 4, pp. 1502–1513, 2014. View at Google Scholar · View at Scopus
  157. T. W. Kensler, T. J. Curphey, Y. Maxiutenko, and B. D. Roebuck, “Chemoprotection by organosulfur inducers of phase 2 enzymes: dithiolethiones and dithiins,” Drug Metabolism and Drug Interactions, vol. 17, no. 1–4, pp. 3–22, 2000. View at Google Scholar · View at Scopus
  158. C. C. Conaway, C.-X. Wang, B. Pittman et al., “Phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A/J mice,” Cancer Research, vol. 65, no. 18, pp. 8548–8557, 2005. View at Publisher · View at Google Scholar · View at Scopus
  159. R. Garg, S. Gupta, and G. B. Maru, “Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action,” Carcinogenesis, vol. 29, no. 5, pp. 1022–1032, 2008. View at Publisher · View at Google Scholar · View at Scopus
  160. R. K. Thimmulappa, T. Rangasamy, J. Alam, and S. Biswal, “Dibenzoylmethane activates Nrf2-dependent detoxification pathway and inhibits benzo(a)pyrene induced DNA adducts in lungs,” Medicinal Chemistry, vol. 4, no. 5, pp. 473–481, 2008. View at Publisher · View at Google Scholar · View at Scopus
  161. B. Singh, R. Shoulson, A. Chatterjee et al., “Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways,” Carcinogenesis, vol. 35, no. 8, pp. 1872–1880, 2014. View at Publisher · View at Google Scholar · View at Scopus
  162. K. M. Chang, F. P. Liang, I. L. Chen et al., “Discovery of oxime-bearing naphthalene derivatives as a novel structural type of Nrf2 activators,” Bioorganic & Medicinal Chemistry, vol. 23, no. 13, pp. 3852–3859, 2015. View at Google Scholar
  163. F.-F. Gan, H. Ling, X. Ang et al., “A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-kappaB and Nrf2-Keap1 signaling pathways,” Toxicology and Applied Pharmacology, vol. 272, no. 3, pp. 852–862, 2013. View at Publisher · View at Google Scholar · View at Scopus
  164. R. Hu, C. L.-L. Saw, R. Yu, and A.-N. T. Kong, “Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory,” Antioxidants and Redox Signaling, vol. 13, no. 11, pp. 1679–1698, 2010. View at Publisher · View at Google Scholar · View at Scopus
  165. C. Li, X. Xu, X. J. Wang, and Y. Pan, “Imine resveratrol analogues: molecular design, Nrf2 activation and SAR analysis,” PLoS ONE, vol. 9, no. 7, Article ID e101455, 2014. View at Publisher · View at Google Scholar · View at Scopus
  166. C. R. Zhao, Z. H. Gao, and X. J. Qu, “Nrf2-ARE signaling pathway and natural products for cancer chemoprevention,” Cancer Epidemiology, vol. 34, no. 5, pp. 523–533, 2010. View at Publisher · View at Google Scholar · View at Scopus
  167. J.-S. Lee and Y.-J. Surh, “Nrf2 as a novel molecular target for chemoprevention,” Cancer Letters, vol. 224, no. 2, pp. 171–184, 2005. View at Publisher · View at Google Scholar · View at Scopus
  168. W.-S. Jeong, M. Jun, and A.-N. T. Kong, “Nrf2: a potential molecular target for cancer chemoprevention by natural compounds,” Antioxidants & Redox Signaling, vol. 8, no. 1-2, pp. 99–106, 2006. View at Publisher · View at Google Scholar · View at Scopus
  169. A. Lau, N. F. Villeneuve, Z. Sun, P. K. Wong, and D. D. Zhang, “Dual roles of Nrf2 in cancer,” Pharmacological Research, vol. 58, no. 5-6, pp. 262–270, 2008. View at Publisher · View at Google Scholar · View at Scopus
  170. T. W. Kensler, J.-G. Chen, P. A. Egner et al., “Effects of glucosinolate-rich broccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenanthrene tetraols in a randomized clinical trial in He Zuo Township, Qidong, People's Republic of China,” Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 11, pp. 2605–2613, 2005. View at Publisher · View at Google Scholar · View at Scopus
  171. F. Shang, L. Hui, X. An, X. Zhang, S. Guo, and Z. Kui, “ZnPPIX inhibits peritoneal metastasis of gastric cancer via its antiangiogenic activity,” Biomedicine & Pharmacotherapy, vol. 71, pp. 240–246, 2015. View at Publisher · View at Google Scholar
  172. S. K. Sahoo, T. Sawa, J. Fang et al., “Pegylated zinc protoporphyrin: a water-soluble heme oxygenase inhibitor with tumor-targeting capacity,” Bioconjugate Chemistry, vol. 13, no. 5, pp. 1031–1038, 2002. View at Publisher · View at Google Scholar · View at Scopus
  173. A. K. Iyer, K. Greish, T. Seki et al., “Polymeric micelles of zinc protoporphyrin for tumor targeted delivery based on EPR effect and singlet oxygen generation,” Journal of Drug Targeting, vol. 15, no. 7-8, pp. 496–506, 2007. View at Publisher · View at Google Scholar · View at Scopus
  174. A. Józkowicz and J. Dulak, “Effects of protoporphyrins on production of nitric oxide and expression of vascular endothelial growth factor in vascular smooth muscle cells and macrophages,” Acta Biochimica Polonica, vol. 50, no. 1, pp. 69–79, 2003. View at Google Scholar · View at Scopus
  175. A. Loboda, A. Jazwa, B. Wegiel, A. Jozkowicz, and J. Dulak, “Heme oxygenase-1-dependent and -independent regulation of angiogenic genes expression: effect of cobalt protoporphyrin and cobalt chloride on VEGF and IL-8 synthesis in human microvascular endothelial cells,” Cellular and Molecular Biology, vol. 51, no. 4, pp. 347–355, 2005. View at Publisher · View at Google Scholar · View at Scopus
  176. J. Busserolles, J. Megías, M. C. Terencio, and M. J. Alcaraz, “Heme oxygenase-1 inhibits apoptosis in Caco-2 cells via activation of Akt pathway,” International Journal of Biochemistry and Cell Biology, vol. 38, no. 9, pp. 1510–1517, 2006. View at Publisher · View at Google Scholar · View at Scopus
  177. J. Fang, T. Sawa, T. Akaike et al., “In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor,” Cancer Research, vol. 63, no. 13, pp. 3567–3574, 2003. View at Google Scholar · View at Scopus
  178. D. Ren, N. F. Villeneuve, T. Jiang et al., “Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 4, pp. 1433–1438, 2011. View at Publisher · View at Google Scholar · View at Scopus
  179. A. Olayanju, I. M. Copple, H. K. Bryan et al., “Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2,” Free Radical Biology and Medicine, vol. 78, pp. 202–212, 2015. View at Publisher · View at Google Scholar · View at Scopus
  180. T. Zhang, Y. Kimura, S. Jiang, K. Harada, Y. Yamashita, and H. Ashida, “Luteolin modulates expression of drug-metabolizing enzymes through the AhR and Nrf2 pathways in hepatic cells,” Archives of Biochemistry and Biophysics, vol. 557, pp. 36–46, 2014. View at Publisher · View at Google Scholar · View at Scopus
  181. X. Tang, H. Wang, L. Fan et al., “Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs,” Free Radical Biology and Medicine, vol. 50, no. 11, pp. 1599–1609, 2011. View at Publisher · View at Google Scholar · View at Scopus
  182. S. Chian, Y.-Y. Li, X.-J. Wang, and X.-W. Tang, “Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway,” Asian Pacific Journal of Cancer Prevention, vol. 15, no. 6, pp. 2911–2916, 2014. View at Publisher · View at Google Scholar · View at Scopus
  183. S. Chian, R. Thapa, Z. Chi, X. J. Wang, and X. Tang, “Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo,” Biochemical and Biophysical Research Communications, vol. 447, no. 4, pp. 602–608, 2014. View at Publisher · View at Google Scholar · View at Scopus
  184. S. Magesh, Y. Chen, and L. Hu, “Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents,” Medicinal Research Reviews, vol. 32, no. 4, pp. 687–726, 2012. View at Publisher · View at Google Scholar · View at Scopus
  185. X. J. Wang, J. D. Hayes, C. J. Henderson, and C. R. Wolf, “Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 49, pp. 19589–19594, 2007. View at Publisher · View at Google Scholar · View at Scopus
  186. M. Valenzuela, C. Glorieux, J. Stockis et al., “Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells,” British Journal of Cancer, vol. 111, no. 5, pp. 874–882, 2014. View at Publisher · View at Google Scholar · View at Scopus
  187. N. Sadeghi, J. L. Abbruzzese, S.-C. J. Yeung, M. Hassan, and D. Li, “Metformin use is associated with better survival of diabetic patients with pancreatic cancer,” Clinical Cancer Research, vol. 18, no. 10, pp. 2905–2912, 2012. View at Publisher · View at Google Scholar · View at Scopus
  188. A. K. MacLeod, M. Mcmahon, S. M. Plummer et al., “Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds,” Carcinogenesis, vol. 30, no. 9, pp. 1571–1580, 2009. View at Publisher · View at Google Scholar · View at Scopus
  189. K.-A. Jung, B.-H. Choi, C.-W. Nam et al., “Identification of aldo-keto reductases as NRF2-target marker genes in human cells,” Toxicology Letters, vol. 218, no. 1, pp. 39–49, 2013. View at Publisher · View at Google Scholar · View at Scopus
  190. A. S. Agyeman, R. Chaerkady, P. G. Shaw et al., “Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles,” Breast Cancer Research and Treatment, vol. 132, no. 1, pp. 175–187, 2012. View at Publisher · View at Google Scholar · View at Scopus
  191. J. Paek, J. Y. Lo, S. D. Narasimhan et al., “Mitochondrial SKN-1/Nrf mediates a conserved starvation response,” Cell Metabolism, vol. 16, no. 4, pp. 526–537, 2012. View at Publisher · View at Google Scholar · View at Scopus
  192. S. A. Chanas, Q. Jiang, M. McMahon et al., “Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice,” Biochemical Journal, vol. 365, no. 2, pp. 405–416, 2002. View at Publisher · View at Google Scholar · View at Scopus
  193. J. M. Maher, M. Z. Dieter, L. M. Aleksunes et al., “Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway,” Hepatology, vol. 46, no. 5, pp. 1597–1610, 2007. View at Publisher · View at Google Scholar · View at Scopus
  194. M. S. Yates, Q. T. Tran, P. M. Dolan et al., “Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice,” Carcinogenesis, vol. 30, no. 6, pp. 1024–1031, 2009. View at Publisher · View at Google Scholar · View at Scopus