Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2017, Article ID 7403747, 12 pages
https://doi.org/10.1155/2017/7403747
Review Article

Apoptotic Signaling Pathways in Glioblastoma and Therapeutic Implications

1Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
2Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
3Unidad Periférica de Investigación en Biomedicina Translacional, ISSSTE C.M.N. 20 de Noviembre, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

Correspondence should be addressed to Marco A. Velasco-Velázquez; xm.manu@ocsalevocram and Aliesha González-Arenas; moc.liamg@zelaznogahseila

Received 28 July 2017; Revised 22 September 2017; Accepted 28 September 2017; Published 12 November 2017

Academic Editor: Francesco Pasqualetti

Copyright © 2017 Silvia Anahi Valdés-Rives 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. D. N. Louis, H. Ohgaki, and O. D. Wiestler, “The 2007 WHO classification of tumours of the central nervous system,” Acta Neuropathologica, vol. 114, no. 2, pp. 97–109, 2007. View at Publisher · View at Google Scholar · View at Scopus
  2. I. A. Ho and W. S. Shim, “Contribution of the microenvironmental niche to glioblastoma heterogeneity,” BioMed Research International, vol. 2017, pp. 1–13, 2017. View at Publisher · View at Google Scholar
  3. R. Stupp, M. E. Hegi, W. P. Mason et al., “Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial,” The Lancet Oncology, vol. 10, no. 5, pp. 459–466, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. A. Sottoriva, I. Spiteri, S. G. M. Piccirillo et al., “Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 110, no. 10, pp. 4009–4014, 2013. View at Publisher · View at Google Scholar · View at Scopus
  5. H. S. Friedman, T. Kerby, and H. Calvert, “Temozolomide and treatment of malignant glioma,” Clinical Cancer Research, vol. 6, no. 7, pp. 2585–2597, 2000. View at Google Scholar · View at Scopus
  6. C. R. Miller and A. Perry, “Glioblastoma: morphologic and molecular genetic diversity,” Archives of Pathology & Laboratory Medicine. College of American Pathologists, vol. 131, pp. 397–406, 2007. View at Google Scholar
  7. H. Ohgaki, P. Dessen, B. Jourde et al., “Genetic pathways to glioblastoma: a population-based study,” Cancer Research, vol. 64, no. 19, pp. 6892–6899, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. J. L. Izquierdo-Garcia, P. Viswanath, P. Eriksson et al., “Metabolic reprogramming in mutant IDH1 glioma cells,” PLoS ONE, vol. 10, no. 2, Article ID e0118781, 2015. View at Publisher · View at Google Scholar · View at Scopus
  9. “Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. Macmillan Publishers Limited. 2008; 455: 1061–8”.
  10. R. G. W. Verhaak, K. A. Hoadley, E. Purdom et al., “Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1,” Cancer Cell, vol. 17, pp. 98–110, 2010. View at Google Scholar
  11. Q.-W. Fan and W. A. Weiss, “Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors,” Methods in Molecular Biology, vol. 821, pp. 349–359, 2012. View at Publisher · View at Google Scholar · View at Scopus
  12. “Phase II Study of BKM120 for subjects with recurrent glioblastoma,” https://clinicaltrials.gov/ct2/show/NCT01339052.
  13. W. J. Wang, L. M. Long, N. Yang et al., “NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro,” Acta Pharmacologica Sinica, vol. 34, no. 5, pp. 681–690, 2013. View at Publisher · View at Google Scholar · View at Scopus
  14. E. Galanis, J. C. Buckner, M. J. Maurer et al., “Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a north central cancer treatment group study,” Journal of Clinical Oncology, vol. 23, no. 23, pp. 5294–5304, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. G. J. Kubicek, M. Werner-Wasik, M. Machtay et al., “Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervous system malignancies,” International Journal of Radiation Oncology, Biology, Physics, vol. 74, no. 2, pp. 433–439, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. I. Coupienne, S. Bontems, M. Dewaele et al., “NF-kappaB inhibition improves the sensitivity of human glioblastoma cells to 5-aminolevulinic acid-based photodynamic therapy,” Biochemical Pharmacology, vol. 81, no. 5, pp. 606–616, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. T. Fukushima, M. Kawaguchi, K. Yorita et al., “Antitumor effect of dehydroxymethylepoxyquinomicin, a small molecule inhibitor of nuclear factor-kB, on glioblastoma,” Neuro-Oncology, vol. 14, no. 1, pp. 19–28, 2012. View at Publisher · View at Google Scholar · View at Scopus
  18. K. E. Tagscherer, A. Fassl, B. Campos et al., “Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins,” Oncogene, vol. 27, no. 52, pp. 6646–6656, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. J. B. Fiveash, S. A. Chowdhary, D. Peereboom et al., “NABTT-0702: A phase II study of R-(-)-gossypol (AT-101) in recurrent glioblastoma multiforme (GBM),” Journal of Clinical Oncology American Society of Clinical Oncology, vol. 27, 2009. View at Google Scholar
  20. G. Karpel-Massler, C. Shu, L. Chau et al., “Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo,” Oncotarget , vol. 6, pp. 14507–14521, 2015. View at Publisher · View at Google Scholar
  21. D. S. Ziegler, R. D. Wright, S. Kesari et al., “Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosis proteins,” The Journal of Clinical Investigation, vol. 118, no. 9, pp. 3109–3122, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. L. Wagner, V. Marschall, S. Karl et al., “Smac mimetic sensitizes glioblastoma cells to Temozolomide-induced apoptosis in a RIP1- and NF-κB-dependent manner,” Oncogene, vol. 32, no. 8, pp. 988–997, 2013. View at Publisher · View at Google Scholar · View at Scopus
  23. S. Fulda, W. Wick, M. Weller, and K.-M. Debatin, “Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo,” Nature Medicine, vol. 8, no. 8, pp. 808–815, 2002. View at Publisher · View at Google Scholar · View at Scopus
  24. M. A. García, A. Ramírez, E. López-Ruiz et al., “Apoptosis as a therapeutic target in cancer and cancer stem cells: novel strategies and futures perspectives. Citeseer; 2012”.
  25. I. M. Ghobrial, T. E. Witzig, and A. A. Adjei, “Targeting apoptosis pathways in cancer therapy,” CA: A Cancer Journal for Clinicians, vol. 55, no. 3, pp. 178–194, 2005. View at Publisher · View at Google Scholar · View at Scopus
  26. L. C. Cantley, “The phosphoinositide 3-kinase pathway,” Science, vol. 296, no. 5573, pp. 1655–1657, 2002. View at Publisher · View at Google Scholar · View at Scopus
  27. T. F. Franke, C. P. Hornik, L. Segev, G. A. Shostak, and C. Sugimoto, “PI3K/Akt and apoptosis: size matters,” Oncogene, vol. 22, no. 56, pp. 8983–8998, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. S. R. Datta, A. Brunet, and M. E. Greenberg, “Cellular survival: a play in three akts,” Genes & Development, vol. 13, no. 22, pp. 2905–2927, 1999. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Mao, D. G. Lebrun, J. Yang, V. F. Zhu, and M. Li, “Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets,” Cancer Investigation, vol. 30, no. 1, pp. 48–56, 2012. View at Publisher · View at Google Scholar · View at Scopus
  30. H. Wang, H. Wang, W. Zhang, H. J. Huang, W. S. L. Liao, and G. N. Fuller, “Analysis of the activation status of Akt, NFκB, and Stat3 in human diffuse gliomas,” Laboratory Investigation, vol. 84, no. 8, pp. 941–951, 2004. View at Publisher · View at Google Scholar · View at Scopus
  31. M.-E. Halatsch, U. Schmidt, A. Unterberg, and V. I. Vougioukas, “Uniform MDM2 overexpression in a panel of glioblastoma multiforme cell lines with divergent EGFR and p53 expression status,” Anticancer Reseach, vol. 26, pp. 4191–4194, 2006. View at Google Scholar · View at Scopus
  32. B. Costa, S. Bendinelli, P. Gabelloni et al., “Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor,” PLoS ONE, vol. 8, no. 8, Article ID e72281, 2013. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Daniele, B. Costa, E. Zappelli et al., “Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells,” Scientific Reports, vol. 5, article 9956, 2015. View at Publisher · View at Google Scholar
  34. S. R. Datta, H. Dudek, T. Xu et al., “Akt phosphorylation of BAD couples survival signals to the cell- intrinsic death machinery,” Cell, vol. 91, no. 2, pp. 231–241, 1997. View at Publisher · View at Google Scholar · View at Scopus
  35. Z. Duzgun, Z. Eroglu, and C. Biray Avci, “Role of mTOR in glioblastoma,” Gene, vol. 575, no. 2, pp. 187–190, 2016. View at Publisher · View at Google Scholar · View at Scopus
  36. L. Lisi, E. Laudati, P. Navarra, and C. Dello Russo, “The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype,” Journal of Neuroinflammation, vol. 11, no. 1, article no. 125, 2014. View at Publisher · View at Google Scholar · View at Scopus
  37. R. Endersby and S. J. Baker, “PTEN signaling in brain: Neuropathology and tumorigenesis,” Oncogene, vol. 27, no. 41, pp. 5416–5430, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. Y. Yang, N. Shao, G. Luo et al., “Mutations of PTEN gene in gliomas correlate to tumor differentiation and short-term survival rate,” Anticancer Reseach, vol. 30, no. 3, pp. 981–985, 2010. View at Google Scholar · View at Scopus
  39. B. K. A. Rasheed, T. T. Stenzel, R. E. McLendon et al., “PTEN gene mutations are seen in high-grade but not in low-grade gliomas,” Cancer Research, vol. 57, no. 19, pp. 4187–4190, 1997. View at Google Scholar · View at Scopus
  40. Y. Yang, N. Shao, G. Luo, L. Li, P. Nilsson-Ehle, and N. Xu, “Relationship between PTEN gene expression and differentiation of human glioma,” Scandinavian Journal of Clinical & Laboratory Investigation, vol. 66, no. 6, pp. 469–475, 2006. View at Publisher · View at Google Scholar · View at Scopus
  41. D. Koul, “PTEN Signaling pathways in glioblastoma,” Cancer Biology & Therapy, vol. 7, no. 9, pp. 1321–1325, 2008. View at Publisher · View at Google Scholar
  42. J.-J. Lee, B. C. Kim, M.-J. Park et al., “PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation,” Cell Death & Differentiation, vol. 18, no. 4, pp. 666–677, 2011. View at Publisher · View at Google Scholar · View at Scopus
  43. V. K. Hill, J. Kim, C. D. James, T. Waldman, and S. Deb, “Correction of PTEN mutations in glioblastoma cell lines via AAV-mediated gene editing,” PLoS ONE, vol. 12, no. 5, Article ID e0176683, 2017. View at Publisher · View at Google Scholar
  44. D. B. T. Cox, R. J. Platt, and F. Zhang, “Therapeutic genome editing: prospects and challenges,” Nature Medicine, vol. 21, no. 2, pp. 121–131, 2015. View at Publisher · View at Google Scholar · View at Scopus
  45. S. Chen, H. Sun, K. Miao, and C.-X. Deng, “CRISPR-Cas9: from genome editing to cancer research,” International Journal of Biological Sciences, vol. 12, no. 12, pp. 1427–1436, 2016. View at Publisher · View at Google Scholar · View at Scopus
  46. N. D. Perkins, “Integrating cell-signalling pathways with NF-kappaB and IKK function,” Nature Reviews Molecular Cell Biology, vol. 8, pp. 49–62, 2007. View at Google Scholar
  47. M. Hinz and C. Scheidereit, “The IκB kinase complex in NF-κB regulation and beyond,” EMBO Reports, vol. 15, no. 1, pp. 46–61, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Chaves, T. Eissing, and F. Allgöwer, “Regulation of apoptosis via the NFκB pathway: modeling and analysis,” in Dynamics on complex networks, N. Ganguly, A. Deuchst, and A. Mukherjee, Eds., Modeling and Simulation in Science, Engineering and Technology, pp. 19–33, Boston, Mass, USA, 2009. View at Publisher · View at Google Scholar · View at MathSciNet
  49. P. Korkolopoulou, G. Levidou, A. A. Saetta et al., “Expression of nuclear factor-κB in human astrocytomas: relation to pIκBa, vascular endothelial growth factor, Cox-2, microvascular characteristics, and survival,” Human Pathology, vol. 39, no. 8, pp. 1143–1152, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. G. P. Atkinson, S. E. Nozell, and E. N. Benveniste, “NF-κB and STAT3 signaling in glioma: Targets for future therapies,” Expert Review of Neurotherapeutics, vol. 10, no. 4, pp. 575–586, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. D. Bai, L. Ueno, and P. K. Vogt, “Akt-mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt,” International Journal of Cancer, vol. 125, no. 12, pp. 2863–2870, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. B. Kaltschmidt, C. Kaltschmidt, T. G. Hofmann, S. P. Hehner, W. Dröge, and M. L. Schmitz, “The pro- or anti-apoptotic function of NF-κB is determined by the nature of the apoptotic stimulus,” European Journal of Biochemistry, vol. 267, no. 12, pp. 3828–3835, 2000. View at Publisher · View at Google Scholar
  53. C.-Y. Wang, M. W. Mayo, R. G. Korneluk, D. V. Goeddel, and A. S. Baldwin Jr., “NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation,” Science, vol. 281, no. 5383, pp. 1680–1683, 1998. View at Publisher · View at Google Scholar · View at Scopus
  54. S. Hayashi, M. Yamamoto, Y. Ueno et al., “Expression of nuclear factor-κB, tumor necrosis factor receptor type 1, and c-Myc in human astrocytomas,” Neurologia Medico-Chirurgica, vol. 41, no. 4, pp. 187–195, 2001. View at Publisher · View at Google Scholar · View at Scopus
  55. “Bortezomib, temozolomide, and regional radiation therapy in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma,” https://www.clinicaltrials.gov/ct2/show/NCT00998010?term=NCT00998010&rank=1.
  56. L. G. Tone, “Inhibition of NF-κB by dehydroxymethylepoxyquinomicin suppresses invasion and synergistically potentiates temozolomide and γ-radiation cytotoxicity in glioblastoma cells,” Chemotherapy Research and Practice, vol. 2013, Article ID 593020, 16 pages, 2013. View at Google Scholar
  57. J. Marie Hardwick and L. Soane, “Multiple functions of BCL-2 family proteins,” Cold Spring Harbor Perspectives in Biology, vol. 5, no. 2, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. D. de Jong, F. A. Prins, D. Y. Mason, J. C. Reed, G. B. van Ommen, and P. M. Kluin, “Subcellular localization of the bcl-2 protein in malignant and normal lymphoid cells,” Cancer Research, vol. 54, no. 1, pp. 256–260, 1994. View at Google Scholar · View at Scopus
  59. S. Cory, D. C. S. Huang, and J. M. Adams, “The Bcl-2 family: roles in cell survival and oncogenesis,” Oncogene, vol. 22, no. 53, pp. 8590–8607, 2003. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Shimizu, M. Narita, and Y. Tsujimoto, “Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC,” Nature, vol. 399, no. 6735, pp. 483–487, 1999. View at Publisher · View at Google Scholar · View at Scopus
  61. B. Qiu, Y. Wang, J. Tao, and Y. Wang, “Expression and correlation of Bcl-2 with pathological grades in human glioma stem cells,” Oncology Reports, vol. 28, no. 1, pp. 155–160, 2012. View at Publisher · View at Google Scholar · View at Scopus
  62. H. Strik, M. Deininger, J. Streffer et al., “BCL-2 family protein expression in initial and recurrent glioblastomas: modulation by radiochemotherapy,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 67, no. 6, pp. 763–768, 1999. View at Publisher · View at Google Scholar · View at Scopus
  63. Z. Jiang, X. Zheng, and K. M. Rich, “Down-regulation of Bcl-2 and Bcl-xL expression with bispecific antisense treatment in glioblastoma cell lines induce cell death,” Journal of Neurochemistry, vol. 84, no. 2, pp. 273–281, 2003. View at Publisher · View at Google Scholar · View at Scopus
  64. V. Voss, C. Senft, V. Lang et al., “The pan-Bcl-2 inhibitor (−)-gossypol triggers autophagic cell death in malignant glioma,” Molecular Cancer Research, vol. 8, no. 7, pp. 1002–1016, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. T. Tencho, A. Zachariou, R. Wilson, M. Ditzel, and P. Meier, “IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms,” Nature Cell Biology, vol. 7, no. 1, pp. 70–77, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. K. H. Khan, M. Blanco-Codesido, and L. R. Molife, “Cancer therapeutics: targeting the apoptotic pathway,” Critical Review in Oncology/Hematology, vol. 90, no. 3, pp. 200–219, 2014. View at Publisher · View at Google Scholar · View at Scopus
  67. R. G. Weber, C. Sommer, F. K. Albert, M. Kiessling, and T. Cremer, “Clinically distinct subgroups of glioblastoma multiforme studied by comparative genomic hybridization,” Laboratory Investigation, vol. 74, no. 1, pp. 108–119, 1996. View at Google Scholar · View at Scopus
  68. W. Yang, M. Cooke, C. S. Duckett, X. Yang, and J. F. Dorsey, “Distinctive effects of the cellular inhibitor of apoptosis protein c-IAP2 through stabilization by XIAP in glioblastoma multiforme cells,” Cell Cycle, vol. 13, no. 6, pp. 992–1005, 2014. View at Publisher · View at Google Scholar · View at Scopus
  69. B. Wagenknecht, T. Glaser, U. Naumann et al., “Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma,” Cell Death & Differentiation, vol. 6, no. 4, pp. 370–376, 1999. View at Publisher · View at Google Scholar · View at Scopus
  70. P. L. C. Lopez, E. C. Filippi-Chiela, A. O. Silva et al., “Sensitization of glioma cells by X-linked inhibitor of apoptosis protein knockdown,” Oncology, vol. 83, no. 2, pp. 75–82, 2012. View at Publisher · View at Google Scholar · View at Scopus
  71. H-N. Zhen, L-W. Li, W. Zhang et al., “Short hairpin RNA targeting survivin inhibits growth and angiogenesis of glioma U251 cells,” International Journal of Oncology, vol. 31, pp. 1111–1118, 1992. View at Google Scholar
  72. T. Sun, N. M. Warrington, J. Luo et al., “Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males,” The Journal of Clinical Investigation, vol. 124, no. 9, pp. 4123–4133, 2014. View at Publisher · View at Google Scholar · View at Scopus
  73. A. P. Patel, I. Tirosh, J. J. Trombetta et al., “Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma,” Science, vol. 344, no. 6190, pp. 1396–1401, 2014. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Greaves and C. C. Maley, “Clonal evolution in cancer,” Nature, vol. 481, no. 7381, pp. 306–313, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. J. N. Rich, “Cancer stem cells: understanding tumor hierarchy and heterogeneity,” Medicine, vol. 95, no. 1, pp. S2–S7, 2016. View at Publisher · View at Google Scholar · View at Scopus
  76. A. R. Safa, M. R. Saadatzadeh, A. A. Cohen-Gadol, K. E. Pollok, and K. Bijangi-Vishehsaraei, “Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs,” Genes & Diseases, vol. 2, no. 2, pp. 152–163, 2015. View at Publisher · View at Google Scholar
  77. A. U. Ahmed, B. Auffinger, and M. S. Lesniak, “Understanding glioma stem cells: rationale, clinical relevance and therapeutic strategies,” Expert Review of Neurotherapeutics, vol. 13, no. 5, pp. 545–555, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. D. V. Brown, G. Filiz, P. M. Daniel et al., “Expression of CD133 and CD44 in glioblastoma stem cells correlates with cell proliferation, phenotype stability and intratumor heterogeneity,” PLoS ONE, vol. 12, no. 2, Article ID e0172791, 2017. View at Publisher · View at Google Scholar · View at Scopus
  79. B. D. Liebelt, T. Shingu, X. Zhou, J. Ren, S. A. Shin, and J. Hu, “Glioma stem cells: signaling, microenvironment, and therapy,” Stem Cells International, vol. 2016, Article ID 7849890, 10 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  80. P. Brescia, B. Ortensi, L. Fornasari, D. Levi, G. Broggi, and G. Pelicci, “CD133 is essential for glioblastoma stem cell maintenance,” Stem Cells, vol. 31, no. 5, pp. 857–869, 2013. View at Publisher · View at Google Scholar · View at Scopus
  81. M. Jhanwar-Uniyal, M. Labagnara, M. Friedman, A. Kwasnicki, and R. Murali, “Glioblastoma: molecular pathways, stem cells and therapeutic targets,” Cancers, vol. 7, no. 2, pp. 538–555, 2015. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Toren, B. Bielorai, J. Jacob-Hirsch et al., “CD133-positive hematopoietic stem cell “sternness” genes contain many genes mutated or abnormally expressed in leukemia,” Stem Cells, vol. 23, no. 8, pp. 1142–1153, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. W. Hilbe, S. Dirnhofer, F. Oberwasserlechner et al., “CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer,” Journal of Clinical Pathology, vol. 57, no. 9, pp. 965–969, 2004. View at Publisher · View at Google Scholar · View at Scopus
  84. I. Shibahara, Y. Sonoda, R. Saito et al., “The expression status of CD133 is associated with the pattern and timing of primary glioblastoma recurrence,” Neuro-Oncology, vol. 15, no. 9, pp. 1151–1159, 2013. View at Publisher · View at Google Scholar · View at Scopus
  85. H. Ponta, L. Sherman, and P. A. Herrlich, “CD44: from adhesion molecules to signalling regulators,” Nature Reviews Molecular Cell Biology, vol. 4, no. 1, pp. 33–45, 2003. View at Publisher · View at Google Scholar · View at Scopus
  86. E. Olsson, G. Honeth, P.-O. Bendahl et al., “CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers,” BMC Cancer, vol. 11, article 418, 2011. View at Publisher · View at Google Scholar · View at Scopus
  87. L. Du, H. Wang, L. He et al., “CD44 is of functional importance for colorectal cancer stem cells,” Clinical Cancer Research, vol. 14, no. 21, pp. 6751–6760, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. Z. Gadhoum, M.-P. Leibovitch, J. Oi et al., “CD44: a new means to inhibit acute myeloid leukemia cell proliferation via p27Kip1,” Blood, vol. 103, no. 3, pp. 1059–1068, 2004. View at Publisher · View at Google Scholar · View at Scopus
  89. A. Pietras, A. M. Katz, E. J. Ekström et al., “Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth,” Cell Stem Cell, vol. 14, no. 3, pp. 357–369, 2014. View at Publisher · View at Google Scholar · View at Scopus
  90. K. C. Wei, C. Y. Huang, P. Y. Chen et al., “Evaluation of the prognostic value of CD44 in glioblastoma multiforme,” Anticancer Research, vol. 30, pp. 253–259, 2010. View at Google Scholar
  91. P. Mao, K. Joshi, J. Li et al., “Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 110, no. 21, pp. 8644–8649, 2013. View at Publisher · View at Google Scholar · View at Scopus
  92. D. V. Brown, P. M. Daniel, G. M. D'Abaco et al., “Coexpression analysis of CD133 and CD44 identifies Proneural and Mesenchymal subtypes of glioblastoma multiforme,” Oncotarget , vol. 6, no. 8, pp. 6267–6280, 2015. View at Publisher · View at Google Scholar · View at Scopus
  93. A. Dubrovska, J. Elliott, R. J. Salamone et al., “Combination therapy targeting both tumor-initiating and differentiated cell populations in prostate carcinoma,” Clinical Cancer Research, vol. 16, no. 23, pp. 5692–5702, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. Y. Hu, R. Guo, J. Wei et al., “Effects of PI3K inhibitor NVP-BKM120 on overcoming drug resistance and eliminating cancer stem cells in human breast cancer cells,” Cell Death & Disease, vol. 6, no. 12, article no e2020, 2015. View at Publisher · View at Google Scholar
  95. M. M. Sherry, A. Reeves, J. K. Wu, and B. H. Cochran, “STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells,” Stem Cells, vol. 27, no. 10, pp. 2383–2392, 2009. View at Publisher · View at Google Scholar · View at Scopus
  96. L. G-H, H. Wei, L. S-Q, H. Ji, and D-L. Wang, “Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells,” International Journal of Oncology, vol. 37, pp. 103–110, 2010. View at Google Scholar
  97. T. Ashizawa, H. Miyata, A. Iizuka et al., “Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma,” International Journal of Oncology, vol. 43, no. 1, pp. 219–227, 2013. View at Publisher · View at Google Scholar · View at Scopus
  98. N. Wu, J. Liu, X. Zhao et al., “Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells,” Tumor Biology, vol. 36, no. 12, pp. 9667–9676, 2015. View at Publisher · View at Google Scholar · View at Scopus
  99. M. M. Lino, A. Merlo, and J.-L. Boulay, “Notch signaling in glioblastoma: a developmental drug target?” BMC Medicine, vol. 8, article no. 72, 2010. View at Publisher · View at Google Scholar · View at Scopus
  100. X. Fan, L. Khaki, T. S. Zhu et al., “NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts,” Stem Cells, vol. 28, no. 1, pp. 5–16, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. J. Kim, J. J. Lee, J. Kim, D. Gardner, and P. A. Beachy, “Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 107, no. 30, pp. 13432–13437, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. E. M. Beauchamp, L. Ringer, G. Bulut et al., “Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway,” The Journal of Clinical Investigation, vol. 121, no. 1, pp. 148–160, 2011. View at Publisher · View at Google Scholar · View at Scopus
  103. D. Ding, K. S. Lim, and C. G. Eberhart, “Arsenic trioxide inhibits Hedgehog, Notch and stem cell properties in glioblastoma neurospheres,” Acta Neuropathologica Communications, vol. 2, no. 1, article no. 31, 2014. View at Publisher · View at Google Scholar · View at Scopus
  104. L. Shi, S. Zhang, K. Feng et al., “MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis,” International Journal of Oncology, vol. 40, no. 1, pp. 119–129, 2012. View at Publisher · View at Google Scholar · View at Scopus
  105. J. Chen, X. Fu, Y. Wan, Z. Wang, D. Jiang, and L. Shi, “miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1,” Tumor Biology, vol. 35, no. 7, pp. 6293–6302, 2014. View at Publisher · View at Google Scholar · View at Scopus
  106. M. Zhou, Z. Liu, Y. Zhao et al., “MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) expression,” The Journal of Biological Chemistry, vol. 285, no. 28, pp. 21496–21507, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. C. Shang, Y. Guo, Y. Hong, Y. Liu, and Y. Xue, “MiR-21 up-regulation mediates glioblastoma cancer stem cells apoptosis and proliferation by targeting FASLG,” Molecular Biology Reports, vol. 42, no. 3, pp. 721–727, 2015. View at Publisher · View at Google Scholar
  108. D. H. Floyd, Y. Zhang, B. K. Dey et al., “Novel anti-apoptotic microRNAs 582-5p and 363 promote human glioblastoma stem cell survival via direct inhibition of caspase 3, caspase 9, and Bim,” PLoS ONE, vol. 9, no. 5, Article ID e96239, 2014. View at Publisher · View at Google Scholar · View at Scopus
  109. S. S. Rathod, S. B. Rani, M. Khan, D. Muzumdar, and A. Shiras, “Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways,” FEBS Open Bio, vol. 4, pp. 485–495, 2014. View at Publisher · View at Google Scholar
  110. Z. Xi, P. Wang, Y. Xue et al., “Overexpression of miR-29a reduces the oncogenic properties of glioblastoma stem cells by downregulating Quaking gene isoform 6,” Oncotarget, vol. 8, pp. 24949–24963, 2017. View at Publisher · View at Google Scholar
  111. N. A. Little, N. D. Hastie, and R. C. Davies, “Identification of WTAP, a novel Wilms' tumour 1-associating protein,” Human Molecular Genetics, vol. 9, no. 15, pp. 2231–2239, 2000. View at Publisher · View at Google Scholar · View at Scopus
  112. C. Englert, X. Hou, S. Maheswaran et al., “WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis,” EMBO Journal, vol. 14, no. 19, pp. 4662–4675, 1995. View at Google Scholar · View at Scopus