Table of Contents Author Guidelines Submit a Manuscript
Journal of Toxicology
Volume 2009, Article ID 785907, 14 pages
http://dx.doi.org/10.1155/2009/785907
Research Article

Deoxycholate, an Endogenous Cytotoxin/Genotoxin, Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis

1Department of Cell Biology & Anatomy, College of Medicine, University of Arizona, Tucson, AZ 85724-5044, USA
2Arizona Cancer Center, University of Arizona, Tucson, AZ 85724-5044, USA
3INCELL Corporation, San Antonio, TX 78249, USA
4Department of Internal Medicine, College of Medicine, University of Arizona, Tucson, AZ 85724-5044, USA
5Southern Arizona Veterans Affairs Health Care System, Tucson, AZ 85723, USA

Received 18 September 2008; Revised 25 January 2009; Accepted 24 February 2009

Academic Editor: Brad Upham

Copyright © 2009 Claire M. Payne 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. P. J. Prichard and J. J. Tjandra, “Colorectal cancer,” The Medical Journal of Australia, vol. 169, no. 9, pp. 493–498, 1998. View at Google Scholar
  2. B. S. Reddy, K. Watanabe, J. H. Weisburger, and E. L. Wynder, “Promoting effect of bile acids in colon carcinogenesis in germ-free and conventional F344 rats,” Cancer Research, vol. 37, no. 9, pp. 3238–3242, 1977. View at Google Scholar
  3. T. M. C. M. De Kok, A. van Faassen, B. Glinghammar et al., “Bile acid concentrations, cytotoxicity, and pH of fecal water from patients with colorectal adenomas,” Digestive Diseases and Sciences, vol. 44, no. 11, pp. 2218–2225, 1999. View at Publisher · View at Google Scholar
  4. P. Y. Cheah, “Hypotheses for the etiology of colorectal cancer—an overview,” Nutrition and Cancer, vol. 14, no. 1, pp. 5–13, 1990. View at Google Scholar
  5. U. G. Allinger, G. K. Johansson, J.-A. Gustafsson, and J. J. Rafter, “Shift from a mixed to a lactovegetarian diet: influence on acidic lipids in fecal water—a potential risk factor for colon cancer,” The American Journal of Clinical Nutrition, vol. 50, no. 5, pp. 992–996, 1989. View at Google Scholar
  6. G. J. S. Jenkins, F. R. D'Souza, S. H. Suzen et al., “Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: the potential role of anti-oxidants in Barrett's oesophagus,” Carcinogenesis, vol. 28, no. 1, pp. 136–142, 2007. View at Publisher · View at Google Scholar
  7. G. J. S. Jenkins, J. Cronin, A. Alhamdani et al., “The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-?B activation in oesophageal cells, with a mechanism of action involving ROS,” Mutagenesis, vol. 23, no. 5, pp. 399–405, 2008. View at Publisher · View at Google Scholar
  8. C. M. Payne, C. Bernstein, K. Dvorak, and H. Bernstein, “Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis,” Clinical and Experimental Gastroenterology, vol. 1, pp. 19–47, 2008. View at Google Scholar
  9. H. Bernstein, C. Bernstein, C. M. Payne, K. Dvorakova, and H. Garewal, “Bile acids as carcinogens in human gastrointestinal cancers,” Mutation Research, vol. 589, no. 1, pp. 47–65, 2005. View at Publisher · View at Google Scholar
  10. C. M. Payne, C. Crowley-Weber, K. Dvorak et al., “Mitochondrial perturbation attenuates bile acid-induced cytotoxicity,” Cell Biology and Toxicology, vol. 21, no. 5-6, pp. 215–231, 2005. View at Publisher · View at Google Scholar
  11. C. M. Payne, C. Weber, C. Crowley-Skillicorn et al., “Deoxycholate induces mitochondrial oxidative stress and activates NF-?B through multiple mechanisms in HCT-116 colon epithelial cells,” Carcinogenesis, vol. 28, no. 1, pp. 215–222, 2007. View at Publisher · View at Google Scholar
  12. R. J. Sokol, R. Dahl, M. W. Devereaux, B. Yerushalmi, G. E. Kobak, and E. Gumpricht, “Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids,” Journal of Pediatric Gastroenterology and Nutrition, vol. 41, no. 2, pp. 235–243, 2005. View at Publisher · View at Google Scholar
  13. D. Washo-Stultz, C. Crowley-Weber, K. Dvorakova et al., “Role of mitochondrial complexes I and II, reactive oxygen species and arachidonic acid metabolism in deoxycholate-induced apoptosis,” Cancer Letters, vol. 177, no. 2, pp. 129–144, 2002. View at Publisher · View at Google Scholar
  14. H. Bernstein, H. Holubec, C. Bernstein et al., “Deoxycholate-induced colitis is markedly attenuated in Nos2 knockout mice in association with modulation of gene expression profiles,” Digestive Diseases and Sciences, vol. 52, no. 3, pp. 628–642, 2007. View at Publisher · View at Google Scholar
  15. D. Washo-Stultz, N. Hoglen, H. Bernstein, C. Bernstein, and C. M. Payne, “Role of nitric oxide and peroxynitrite in bile salt-induced apoptosis: relevance to colon carcinogenesis,” Nutrition and Cancer, vol. 35, no. 2, pp. 180–188, 1999. View at Publisher · View at Google Scholar
  16. A. P. Rolo, C. M. Palmeira, J. M. Holy, and K. B. Wallace, “Role of mitochondrial dysfunction in combined bile acid-induced cytotoxicity: the switch between apoptosis and necrosis,” Toxicological Sciences, vol. 79, no. 1, pp. 196–204, 2004. View at Publisher · View at Google Scholar
  17. H. Bernstein, H. Holubec, C. Bernstein et al., “Unique dietary-related mouse model of colitis,” Inflammatory Bowel Diseases, vol. 12, no. 4, pp. 278–293, 2006. View at Publisher · View at Google Scholar
  18. B. Glinghammar, H. Inoue, and J. J. Rafter, “Deoxycholic acid causes DNA damage in colonic cells with subsequent induction of caspases, COX-2 promoter activity and the transcription factors NF-κB and AP-1,” Carcinogenesis, vol. 23, no. 5, pp. 839–845, 2002. View at Publisher · View at Google Scholar
  19. P. Rosignoli, R. Fabiani, A. De Bartolomeo, R. Fuccelli, M. A. Pelli, and G. Morozzi, “Genotoxic effect of bile acids on human normal and tumour colon cells and protection by dietary antioxidants and butyrate,” European Journal of Nutrition, vol. 47, no. 6, pp. 301–309, 2008. View at Publisher · View at Google Scholar
  20. C. M. Payne, C. Crowley, D. Washo-Stultz et al., “The stress-response proteins poly(ADP-ribose) polymerase and NF-?B protect against bile salt-induced apoptosis,” Cell Death & Differentiation, vol. 5, no. 7, pp. 623–636, 1998. View at Google Scholar
  21. C. M. Payne, C. N. Waltmire, C. Crowley et al., “Caspase-6 mediated cleavage of guanylate cyclase a1 during deoxycholate-induced apoptosis: protective role of the nitric oxide signaling module,” Cell Biology and Toxicology, vol. 19, no. 6, pp. 373–392, 2003. View at Publisher · View at Google Scholar
  22. G. J. S. Jenkins, K. Harries, S. H. Doak et al., “The bile acid deoxycholic acid (DCA) at neutral pH activates NF-?B and induces IL-8 expression in oesophageal cells in vitro,” Carcinogenesis, vol. 25, no. 3, pp. 317–323, 2004. View at Publisher · View at Google Scholar
  23. D. J. Turner, S. M. Alaish, T. Zou, J. N. Rao, J.-Y. Wang, and E. D. Strauch, “Bile salts induce resistance to apoptosis through NF-κB-mediated XIAP expression,” Annals of Surgery, vol. 245, no. 3, pp. 415–425, 2007. View at Publisher · View at Google Scholar
  24. A. Kelekar, “Autophagy,” Annals of the New York Academy of Sciences, vol. 1066, pp. 259–271, 2005. View at Publisher · View at Google Scholar
  25. B. Levine, “Eating oneself and uninvited guests: autophagy-related pathways in cellular defense,” Cell, vol. 120, no. 2, pp. 159–162, 2005. View at Publisher · View at Google Scholar
  26. N. Mizushima and D. J. Klionsky, “Protein turnover via autophagy: implications for metabolism,” Annual Review of Nutrition, vol. 27, pp. 19–40, 2007. View at Publisher · View at Google Scholar
  27. J. J. Lemasters, “Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging,” Rejuvenation Research, vol. 8, no. 1, pp. 3–5, 2005. View at Publisher · View at Google Scholar
  28. S. Bernales, S. Schuck, and P. Walter, “ER-phagy: selective autophagy of the endoplasmic reticulum,” Autophagy, vol. 3, no. 3, pp. 285–287, 2007. View at Google Scholar
  29. I. Beau, A. Esclatine, and P. Codogno, “Lost to translation: when autophagy targets mature ribosomes,” Trends in Cell Biology, vol. 18, no. 7, pp. 311–314, 2008. View at Publisher · View at Google Scholar
  30. T. Kawamata, Y. Kamada, Y. Kabeya, T. Sekito, and Y. Ohsumi, “Organization of the pre-autophagosomal structure responsible for autophagosome formation,” Molecular Biology of the Cell, vol. 19, no. 5, pp. 2039–2050, 2008. View at Publisher · View at Google Scholar
  31. Z. Xie and D. J. Klionsky, “Autophagosome formation: core machinery and adaptations,” Nature Cell Biology, vol. 9, no. 10, pp. 1102–1109, 2007. View at Publisher · View at Google Scholar
  32. Y. Ohsumi, “Molecular dissection of autophagy: two ubiquitin-like systems,” Nature Reviews Molecular Cell Biology, vol. 2, no. 3, pp. 211–216, 2001. View at Publisher · View at Google Scholar
  33. A. J. Meijer and P. Codogno, “Regulation and role of autophagy in mammalian cells,” The International Journal of Biochemistry & Cell Biology, vol. 36, no. 12, pp. 2445–2462, 2004. View at Publisher · View at Google Scholar
  34. A. M. Cuervo, “Autophagy: many paths to the same end,” Molecular and Cellular Biochemistry, vol. 263, no. 1, pp. 55–72, 2004. View at Publisher · View at Google Scholar
  35. D. J. Klionsky, “Autophagy: from phenomenology to molecular understanding in less than a decade,” Nature Reviews Molecular Cell Biology, vol. 8, no. 11, pp. 931–937, 2007. View at Publisher · View at Google Scholar
  36. M. J. Abedin, D. Wang, M. A. McDonnell, U. Lehmann, and A. Kelekar, “Autophagy delays apoptotic death in breast cancer cells following DNA damage,” Cell Death & Differentiation, vol. 14, no. 3, pp. 500–510, 2007. View at Publisher · View at Google Scholar
  37. R. K. Amaravadi, D. Yu, J. J. Lum et al., “Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma,” The Journal of Clinical Investigation, vol. 117, no. 2, pp. 326–336, 2007. View at Publisher · View at Google Scholar
  38. J. Botti, M. Djavaheri-Mergny, Y. Pilatte, and P. Codogno, “Autophagy signaling and the cogwheels of cancer,” Autophagy, vol. 2, no. 2, pp. 67–73, 2006. View at Google Scholar
  39. K. Sato, K. Tsuchihara, S. Fujii et al., “Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation,” Cancer Research, vol. 67, no. 20, pp. 9677–9684, 2007. View at Publisher · View at Google Scholar
  40. C. Crowley-Weber, C. M. Payne, M. Gleason-Guzman et al., “Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate,” Carcinogenesis, vol. 23, no. 12, pp. 2063–2080, 2002. View at Publisher · View at Google Scholar
  41. J.-H. Lim, J.-W. Park, M.-S. Kim, S.-K. Park, R. S. Johnson, and Y.-S. Chun, “Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxia-inducible factor-1α,” Molecular Pharmacology, vol. 70, no. 6, pp. 1856–1865, 2006. View at Publisher · View at Google Scholar
  42. J. J. Shacka, B. J. Klocke, and K. A. Roth, “Autophagy, bafilomycin and cell death: the “A-B-Cs” of plecomacrolide-induced neuroprotection,” Autophagy, vol. 2, no. 3, pp. 228–230, 2006. View at Google Scholar
  43. I. Tanida, N. Minematsu-Ikeguchi, T. Ueno, and E. Kominami, “Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy,” Autophagy, vol. 1, no. 2, pp. 84–91, 2005. View at Google Scholar
  44. A. Gozin, E. Franzini, V. Andrieu, L. Da Costa, E. Rollet-Labelle, and C. Pasquier, “Reactive oxygen species activate focal adhesion kinase, paxillin and P130CAS tyrosine phosphorylation in endothelial cells,” Free Radical Biology & Medicine, vol. 25, no. 9, pp. 1021–1032, 1998. View at Publisher · View at Google Scholar
  45. A. M. Samuni, M. Afeworki, W. Stein et al., “Multifunctional antioxidant activity of HBED iron chelator,” Free Radical Biology & Medicine, vol. 30, no. 2, pp. 170–177, 2001. View at Publisher · View at Google Scholar
  46. A. R. Martirosyan, R. Rahim-Bata, A. B. Freeman, C. D. Clarke, R. L. Howard, and J. S. Strobl, “Differentiation-inducing quinolines as experimental breast cancer agents in the MCF-7 human breast cancer cell model,” Biochemical Pharmacology, vol. 68, no. 9, pp. 1729–1738, 2004. View at Publisher · View at Google Scholar
  47. R. T. Sawyer, D. R. Dobis, M. Goldstein et al., “Beryllium-stimulated reactive oxygen species and macrophage apoptosis,” Free Radical Biology & Medicine, vol. 38, no. 7, pp. 928–937, 2005. View at Publisher · View at Google Scholar
  48. D. Washo-Stultz, C. Crowley, C. M. Payne et al., “Increased susceptibility of cells to inducible apoptosis during growth from early to late log phase: an important caveat for in vitro apoptosis research,” Toxicology Letters, vol. 116, no. 3, pp. 199–207, 2000. View at Publisher · View at Google Scholar
  49. C. Liang, P. Feng, B. Ku et al., “Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG,” Nature Cell Biology, vol. 8, no. 7, pp. 688–698, 2006. View at Publisher · View at Google Scholar
  50. Q. Yan, M. Briehl, C. L. Crowley, C. M. Payne, H. Bernstein, and C. Bernstein, “The NAD+ precursors, nicotinic acid and nicotinamide upregulate glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase mRNA in Jurkat cells,” Biochemical and Biophysical Research Communications, vol. 255, no. 1, pp. 133–136, 1999. View at Publisher · View at Google Scholar
  51. L. Qi and K. H. Sit, “Housekeeping genes commanded to commit suicide in CpG-cleavage commitment upstream of Bcl-2 inhibition in caspase-dependent and -independent pathways,” Molecular Cell Biology Research Communications, vol. 3, no. 5, pp. 319–327, 2000. View at Publisher · View at Google Scholar
  52. H. Holubec, C. M. Payne, H. Bernstein et al., “Assessment of apoptosis by immunohistochemical markers compared to cellular morphology in ex vivo-stressed colonic mucosa,” Journal of Histochemistry and Cytochemistry, vol. 53, no. 2, pp. 229–235, 2005. View at Publisher · View at Google Scholar
  53. N. Mizushima, “Methods for monitoring autophagy,” The International Journal of Biochemistry & Cell Biology, vol. 36, no. 12, pp. 2491–2502, 2004. View at Publisher · View at Google Scholar
  54. Y. Kabeya, N. Mizushima, A. Yamamoto, S. Oshitani-Okamoto, Y. Ohsumi, and T. Yoshimori, “LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation,” Journal of Cell Science, vol. 117, no. 13, pp. 2805–2812, 2004. View at Publisher · View at Google Scholar
  55. M. R. Karim, T. Kanazawa, Y. Daigaku, S. Fujimura, G. Miotto, and M. Kadowaki, “Cytosolic LC3 ratio as a sensitive index of macroautophagy in isolated rat hepatocytes and H4-II-E cells,” Autophagy, vol. 3, no. 6, pp. 553–560, 2007. View at Google Scholar
  56. A. A. Ellington, M. Berhow, and K. W. Singletary, “Induction of macroautophagy in human colon cancer cells by soybean B-group triterpenoid saponins,” Carcinogenesis, vol. 26, no. 1, pp. 159–167, 2005. View at Publisher · View at Google Scholar
  57. E. T. Bampton, C. G. Goemans, D. Niranjan, N. Mizushima, and A. M. Tolkovsky, “The dynamics of autophagy visualized in live cells: from autophagosome formation to fusion with endo/lysosomes,” Autophagy, vol. 1, no. 1, pp. 23–36, 2005. View at Google Scholar
  58. Y. Kondo and S. Kondo, “Autophagy and cancer therapy,” Autophagy, vol. 2, no. 2, pp. 85–90, 2006. View at Google Scholar
  59. A. Kihara, Y. Kabeya, Y. Ohsumi, and T. Yoshimori, “Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network,” EMBO Reports, vol. 2, no. 4, pp. 330–335, 2001. View at Publisher · View at Google Scholar
  60. M. Zamocky, P. G. Furtmüller, and C. Obinger, “Evolution of catalases from bacteria to humans,” Antioxidants & Redox Signaling, vol. 10, no. 9, pp. 1527–1547, 2008. View at Publisher · View at Google Scholar
  61. M. Zahmatkesh, M. Kadkhodaee, S. M. S. Moosavi et al., “Beneficial effects of MnTBAP, a broad-spectrum reactive species scavenger, in rat renal ischemia/reperfusion injury,” Clinical and Experimental Nephrology, vol. 9, no. 3, pp. 212–218, 2005. View at Publisher · View at Google Scholar
  62. I. Batinic-Haberle, S. Cuzzocrea, J. S. Rebouças et al., “Pure MnTBAP selectively scavenges peroxynitrite over superoxide: comparison of pure and commercial MnTBAP samples to MnTE-2-PyP in two models of oxidative stress injury, an SOD-specific Escherichia coli model and carrageenan-induced pleurisy,” Free Radical Biology & Medicine, vol. 46, no. 2, pp. 192–201, 2009. View at Publisher · View at Google Scholar
  63. S. W. Leuthauser, L. W. Oberley, T. D. Oberley, J. R. Sorenson, and K. Ramakrishna, “Antitumor effect of a copper coordination compound with superoxide dismutase-like activity,” Journal of the National Cancer Institute, vol. 66, no. 6, pp. 1077–1081, 1981. View at Google Scholar
  64. A. L. Edinger, C. M. Linardic, G. G. Chiang, C. B. Thompson, and R. T. Abraham, “Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells,” Cancer Research, vol. 63, no. 23, pp. 8451–8460, 2003. View at Google Scholar
  65. P. O. Seglen and P. B. Gordon, “3-methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 6, pp. 1889–1892, 1982. View at Publisher · View at Google Scholar
  66. H. Bernstein, C. M. Payne, K. Kunke et al., “A proteomic study of resistance to deoxycholate-induced apoptosis,” Carcinogenesis, vol. 25, no. 5, pp. 681–692, 2004. View at Publisher · View at Google Scholar
  67. P. Boya, R.-A. González-Polo, N. Casares et al., “Inhibition of macroautophagy triggers apoptosis,” Molecular and Cellular Biology, vol. 25, no. 3, pp. 1025–1040, 2005. View at Publisher · View at Google Scholar
  68. A. Yamamoto, Y. Tagawa, T. Yoshimori, Y. Moriyama, R. Masaki, and Y. Tashiro, “Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells,” Cell Structure and Function, vol. 23, no. 1, pp. 33–42, 1998. View at Google Scholar
  69. J. Hong, Y. Nakano, A. Yokomakura et al., “Nitric oxide production by the vacuolar-type (H+)-ATPase inhibitors bafilomycin A1 and concanamycin A and its possible role in apoptosis in RAW 264.7 cells,” The Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 2, pp. 672–681, 2006. View at Publisher · View at Google Scholar
  70. G. Mariño, J. A. Uría, X. S. Puente, V. Quesada, J. Bordallo, and C. López-Otín, “Human autophagins, a family of cysteine proteinases potentially implicated in cell degradation by autophagy,” The Journal of Biological Chemistry, vol. 278, no. 6, pp. 3671–3678, 2003. View at Publisher · View at Google Scholar
  71. R. Scherz-Shouval, E. Shvets, E. Fass, H. Shorer, L. Gil, and Z. Elazar, “Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4,” The EMBO Journal, vol. 26, no. 7, pp. 1749–1760, 2007. View at Publisher · View at Google Scholar
  72. M. Høyer-Hansen and M. Jäättelä, “Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium,” Cell Death & Differentiation, vol. 14, no. 9, pp. 1576–1582, 2007. View at Publisher · View at Google Scholar
  73. M. Katayama, T. Kawaguchi, M. S. Berger, and R. O. Pieper, “DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells,” Cell Death & Differentiation, vol. 14, no. 3, pp. 548–558, 2007. View at Publisher · View at Google Scholar
  74. M. Ogata, S.-I. Hino, A. Saito et al., “Autophagy is activated for cell survival after endoplasmic reticulum stress,” Molecular and Cellular Biology, vol. 26, no. 24, pp. 9220–9231, 2006. View at Publisher · View at Google Scholar
  75. S. Rodriguez-Enriquez, L. He, and J. J. Lemasters, “Role of mitochondrial permeability transition pores in mitochondrial autophagy,” The International Journal of Biochemistry & Cell Biology, vol. 36, no. 12, pp. 2463–2472, 2004. View at Publisher · View at Google Scholar
  76. R. Kiffin, U. Bandyopadhyay, and A. M. Cuervo, “Oxidative stress and autophagy,” Antioxidants & Redox Signaling, vol. 8, no. 1-2, pp. 152–162, 2006. View at Publisher · View at Google Scholar
  77. S. Kametaka, T. Okano, M. Ohsumi, and Y. Ohsumi, “Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae,” The Journal of Biological Chemistry, vol. 273, no. 35, pp. 22284–22291, 1998. View at Publisher · View at Google Scholar
  78. M. Mari and F. Reggiori, “Shaping membranes into autophagosomes,” Nature Cell Biology, vol. 9, no. 10, pp. 1125–1127, 2007. View at Publisher · View at Google Scholar
  79. B. Levine, S. Sinha, and G. Kroemer, “Bcl-2 family members: dual regulators of apoptosis and autophagy,” Autophagy, vol. 4, no. 5, pp. 600–606, 2008. View at Google Scholar
  80. S. Pattingre, L. Espert, M. Biard-Piechaczyk, and P. Codogno, “Regulation of macroautophagy by mTOR and Beclin 1 complexes,” Biochimie, vol. 90, no. 2, pp. 313–323, 2008. View at Publisher · View at Google Scholar
  81. C. H. Ahn, E. G. Jeong, J. W. Lee et al., “Expression of Beclin-1, an autophagy-related protein, in gastric and colorectal cancers,” APMIS: Acta Pathologica, Microbiologica et Immunologica Scandinavica, vol. 115, no. 12, pp. 1344–1349, 2007. View at Publisher · View at Google Scholar
  82. Z. Yue, S. Jin, C. Yang, A. J. Levine, and N. Heintz, “Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 15077–15082, 2003. View at Publisher · View at Google Scholar
  83. X. Qu, J. Yu, G. Bhagat et al., “Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene,” The Journal of Clinical Investigation, vol. 112, no. 12, pp. 1809–1820, 2003. View at Publisher · View at Google Scholar
  84. F. Daniel, A. Legrand, D. Pessayre, N. Vadrot, V. Descatoire, and D. Bernuau, “Partial Beclin 1 silencing aggravates doxorubicin- and Fas-induced apoptosis in HepG2 cells,” World Journal of Gastroenterology, vol. 12, no. 18, pp. 2895–2900, 2006. View at Google Scholar
  85. Y. Cao and D. J. Klionsky, “Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein,” Cell Research, vol. 17, no. 10, pp. 839–849, 2007. View at Publisher · View at Google Scholar
  86. J. Wang, “Beclin 1 bridges autophagy, apoptosis and differentiation,” Autophagy, vol. 4, no. 7, pp. 947–948, 2008. View at Google Scholar
  87. Y.-T. Wu, H.-L. Tan, Q. Huang et al., “Autophagy plays a protective role during zVAD-induced necrotic cell death,” Autophagy, vol. 4, no. 4, pp. 457–466, 2008. View at Google Scholar
  88. F. Scarlatti, C. Bauvy, A. Ventruti et al., “Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of Beclin 1,” The Journal of Biological Chemistry, vol. 279, no. 18, pp. 18384–18391, 2004. View at Publisher · View at Google Scholar
  89. D.-D. Li, L.-L. Wang, R. Deng et al., “The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells,” Oncogene, vol. 28, no. 6, pp. 886–898, 2009. View at Publisher · View at Google Scholar
  90. S. Gupta, R. Natarajan, S. G. Payne et al., “Deoxycholic acid activates the c-Jun N-terminal kinase pathway via FAS receptor activation in primary hepatocytes: role of acidic sphingomyelinase-mediated ceramide generation in FAS receptor activation,” The Journal of Biological Chemistry, vol. 279, no. 7, pp. 5821–5828, 2004. View at Publisher · View at Google Scholar
  91. S. Becker, R. Reinehr, D. Graf, S. vom Dahl, and D. Häussinger, “Hydrophobic bile salts induce hepatocyte shrinkage via NADPH oxidase activation,” Cellular Physiology and Biochemistry, vol. 19, no. 1–4, pp. 89–98, 2007. View at Publisher · View at Google Scholar
  92. S. Becker, R. Reinehr, S. Grether-Beck, A. Eberle, and D. Häussinger, “Hydrophobic bile salts trigger ceramide formation through endosomal acidification,” Biological Chemistry, vol. 388, no. 2, pp. 185–196, 2007. View at Publisher · View at Google Scholar
  93. R. Kannan, M. Jin, M.-A. Gamulescu, and D. R. Hinton, “Ceramide-induced apoptosis: role of catalase and hepatocyte growth factor,” Free Radical Biology & Medicine, vol. 37, no. 2, pp. 166–175, 2004. View at Publisher · View at Google Scholar
  94. S. Corda, C. Laplace, E. Vicaut, and J. Duranteau, “Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-α is mediated by ceramide,” American Journal of Respiratory Cell and Molecular Biology, vol. 24, no. 6, pp. 762–768, 2001. View at Google Scholar
  95. S. Therade-Matharan, E. Laemmel, S. Carpentier et al., “Reactive oxygen species production by mitochondria in endothelial cells exposed to reoxygenation after hypoxia and glucose depletion is mediated by ceramide,” American Journal of Physiology, vol. 289, no. 6, pp. R1756–R1762, 2005. View at Publisher · View at Google Scholar
  96. X.-F. Zhang, B.-X. Li, C.-Y. Dong, and R. Ren, “Apoptosis of human colon carcinoma HT-29 cells induced by ceramide,” World Journal of Gastroenterology, vol. 12, no. 22, pp. 3581–3584, 2006. View at Google Scholar
  97. J. Yu, S. A. Novgorodov, D. Chudakova et al., “JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction,” The Journal of Biological Chemistry, vol. 282, no. 35, pp. 25940–25949, 2007. View at Publisher · View at Google Scholar
  98. J. Villena, M. Henriquez, V. Torres et al., “Ceramide-induced formation of ROS and ATP depletion trigger necrosis in lymphoid cells,” Free Radical Biology & Medicine, vol. 44, no. 6, pp. 1146–1160, 2008. View at Publisher · View at Google Scholar
  99. R. Scherz-Shouval and Z. Elazar, “ROS, mitochondria and the regulation of autophagy,” Trends in Cell Biology, vol. 17, no. 9, pp. 422–427, 2007. View at Publisher · View at Google Scholar
  100. S. Jean-Louis, S. Akare, M. A. Ali, E. A. Mash Jr., E. Meuillet, and J. D. Martinez, “Deoxycholic acid induces intracellular signaling through membrane perturbations,” The Journal of Biological Chemistry, vol. 281, no. 21, pp. 14948–14960, 2006. View at Publisher · View at Google Scholar
  101. C. D. Pacheco and A. P. Lieberman, “Lipid trafficking defects increase Beclin-1 and activate autophagy in Niemann-Pick type C disease,” Autophagy, vol. 3, no. 5, pp. 487–489, 2007. View at Google Scholar
  102. M. B. Azad, Y. Chen, and S. B. Gibson, “Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment,” Antioxidants & Redox Signaling, vol. 11, no. 4, pp. 777–790, 2009. View at Publisher · View at Google Scholar
  103. Y. Chen, E. McMillan-Ward, J. Kong, S. J. Israels, and S. B. Gibson, “Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells,” Cell Death & Differentiation, vol. 15, no. 1, pp. 171–182, 2008. View at Publisher · View at Google Scholar
  104. J. Yang, L.-J. Wu, S.-I. Tashino, S. Onodera, and T. Ikejima, “Reactive oxygen species and nitric oxide regulate mitochondria-dependent apoptosis and autophagy in evodiamine-treated human cervix carcinoma HeLa cells,” Free Radical Research, vol. 42, no. 5, pp. 492–504, 2008. View at Publisher · View at Google Scholar
  105. L. Cao, J. Xu, Y. Lin, X. Zhao, X. Liu, and Z. Chi, “Autophagy is upregulated in rats with status epilepticus and partly inhibited by Vitamin E,” Biochemical and Biophysical Research Communications, vol. 379, no. 4, pp. 949–953, 2009. View at Publisher · View at Google Scholar
  106. J. Li, N. Hou, A. Faried, S. Tsutsumi, T. Takeuchi, and H. Kuwano, “Inhibition of autophagy by 3-MA enhances the effect of 5-FU-induced apoptosis in colon cancer cells,” Annals of Surgical Oncology, vol. 16, no. 3, pp. 761–771, 2009. View at Publisher · View at Google Scholar
  107. B. H. O'Neil and R. M. Goldberg, “Innovations in chemotherapy for metastatic colorectal cancer: an update of recent clinical trials,” Oncologist, vol. 13, no. 10, pp. 1074–1083, 2008. View at Publisher · View at Google Scholar
  108. E. Ersoy, H. Akbulut, and G. Moray, “Effects of oxaliplatin and 5-fluorouracil on the healing of colon anastomoses,” Surgery Today, vol. 39, no. 1, pp. 38–43, 2009. View at Publisher · View at Google Scholar