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標題: ATF3 在 Prodigiosin 誘發之細胞凋亡中所扮演的角色
The Role of ATF3 in Prodigiosin-induced Apoptosis
作者: 彭昱達
Peng, Yu-Ta
關鍵字: ATF3
細胞凋亡
Activating transcription factor 3
PG
Prodigiosin
ER stress
JNK
靈菌紅素
內質網壓力
肺癌
乳癌
出版社: 生物醫學研究所
引用: 1. 台灣行政院衛生署疾病管制局, 98年死因統計. 2010. 2. CDC, Number of deaths for leading causes of death. 2009. 3. WHO, The top 10 causes of death. 2008. 4. WHO, Cancer. 2009. 5. Hanahan, D. and R.A. Weinberg, The hallmarks of cancer. Cell, 2000. 100(1): p. 57-70. 6. Soto-Cerrato, V., et al., Mitochondria-mediated apoptosis operating irrespective of multidrug resistance in breast cancer cells by the anticancer agent prodigiosin. Biochem Pharmacol, 2004. 68(7): p. 1345-52. 7. Fesik, S.W., Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer, 2005. 5(11): p. 876-85. 8. Khan, N., F. Afaq, and H. Mukhtar, Apoptosis by dietary factors: the suicide solution for delaying cancer growth. Carcinogenesis, 2007. 28(2): p. 233-9. 9. Clinical practice guidelines in oncology. National Comprehensive Cancer Network, 2008. 10. 張正雄, 乳癌. 11. 乳癌研究委員會, 乳癌診斷與治療共識. 國家衛生研究院, 2004. 12. MERCK, Lung Carcinoma. 2007. 13. Warr, D.G., Chemotherapy- and cancer-related nausea and vomiting. Curr Oncol, 2008. 15(Supplement 1): p. S4-9. 14. Definition of targeted therapy. National Cancer Institute, 2009. 15. Katzel, J.A., M.P. Fanucchi, and Z. Li, Recent advances of novel targeted therapy in non-small cell lung cancer. J Hematol Oncol, 2009. 2: p. 2. 16. Warr, M.R. and G.C. Shore, Small-molecule Bcl-2 antagonists as targeted therapy in oncology. Curr Oncol, 2008. 15(6): p. 256-61. 17. Jordan, V.C., Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer, 2008. 44(1): p. 30-8. 18. F.D.A. panel Supports Avastin to Treat Brain Tumor. The New York Times, 2009. 19. Furstner, A., Chemistry and biology of roseophilin and the prodigiosin alkaloids: a survey of the last 2500 years. Angew Chem Int Ed Engl, 2003. 42(31): p. 3582-603. 20. Perez-Tomas, R., et al., The prodigiosins, proapoptotic drugs with anticancer properties. Biochem Pharmacol, 2003. 66(8): p. 1447-52. 21. Williamson, N.R., et al., Biosynthesis of the red antibiotic, prodigiosin, in Serratia: identification of a novel 2-methyl-3-n-amyl-pyrrole (MAP) assembly pathway, definition of the terminal condensing enzyme, and implications for undecylprodigiosin biosynthesis in Streptomyces. Mol Microbiol, 2005. 56(4): p. 971-89. 22. Melvin, M.S., et al., Influence of the a-ring on the proton affinity and anticancer properties of the prodigiosins. Chem Res Toxicol, 2002. 15(5): p. 734-41. 23. Melvin, M.S., et al., Influence of the a-ring on the redox and nuclease properties of the prodigiosins: importance of the bipyrrole moiety in oxidative DNA cleavage. Chem Res Toxicol, 2002. 15(5): p. 742-8. 24. Melvin, M.S., et al., Copper-nuclease efficiency correlates with cytotoxicity for the 4-methoxypyrrolic natural products. J Inorg Biochem, 2001. 87(3): p. 129-35. 25. Furstner, A. and E.J. Grabowski, Studies on DNA cleavage by cytotoxic pyrrole alkaloids reveal the distinctly different behavior of roseophilin and prodigiosin derivatives. Chembiochem, 2001. 2(9): p. 706-9. 26. Hecht, S.M., Bleomycin: new perspectives on the mechanism of action. J Nat Prod, 2000. 63(1): p. 158-68. 27. Pogozelski, W.K. and T.D. Tullius, Oxidative Strand Scission of Nucleic Acids: Routes Initiated by Hydrogen Abstraction from the Sugar Moiety. Chem Rev, 1998. 98(3): p. 1089-1108. 28. Burger, R.M., Cleavage of Nucleic Acids by Bleomycin. Chem Rev, 1998. 98(3): p. 1153-1170. 29. Hertzberg, R.P. and P.B. Dervan, Cleavage of DNA with methidiumpropyl-EDTA-iron(II): reaction conditions and product analyses. Biochemistry, 1984. 23(17): p. 3934-45. 30. Lee, K.A., et al., A cellular protein, activating transcription factor, activates transcription of multiple E1A-inducible adenovirus early promoters. Proc Natl Acad Sci U S A, 1987. 84(23): p. 8355-9. 31. Lin, Y.S. and M.R. Green, Interaction of a common cellular transcription factor, ATF, with regulatory elements in both E1a- and cyclic AMP-inducible promoters. Proc Natl Acad Sci U S A, 1988. 85(10): p. 3396-400. 32. Bokar, J.A., et al., Characterization of the cAMP responsive elements from the genes for the alpha-subunit of glycoprotein hormones and phosphoenolpyruvate carboxykinase (GTP). Conserved features of nuclear protein binding between tissues and species. J Biol Chem, 1988. 263(36): p. 19740-7. 33. Roesler, W.J., G.R. Vandenbark, and R.W. Hanson, Cyclic AMP and the induction of eukaryotic gene transcription. J Biol Chem, 1988. 263(19): p. 9063-6. 34. Hai, T. and M.G. Hartman, The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene, 2001. 273(1): p. 1-11. 35. Liang, G., et al., ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem, 1996. 271(3): p. 1695-701. 36. Chen, B.P., et al., ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms. J Biol Chem, 1994. 269(22): p. 15819-26. 37. Murata, R., et al., Extracorporeal shockwaves induce the expression of ATF3 and GAP-43 in rat dorsal root ganglion neurons. Auton Neurosci, 2006. 128(1-2): p. 96-100. 38. Tsujino, H., et al., Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury. Mol Cell Neurosci, 2000. 15(2): p. 170-82. 39. Hai, T., et al., ATF3 and stress responses. Gene Expr, 1999. 7(4-6): p. 321-35. 40. Yin, T., et al., Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem, 1997. 272(32): p. 19943-50. 41. Zhang, C., et al., Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine. Biochem Biophys Res Commun, 2001. 289(3): p. 718-24. 42. Wang, H., et al., Activating transcription factor 3 activates p53 by preventing E6-associated protein from binding to E6. J Biol Chem, 2010. 285(17): p. 13201-10. 43. Mo, P., et al., MDM2 mediates ubiquitination and degradation of activating transcription factor 3. J Biol Chem, 2010. 44. Lee, S.H., et al., Activating transcription factor 2 (ATF2) controls tolfenamic acid-induced ATF3 expression via MAP kinase pathways. Oncogene, 2010. 45. Tian, Z., et al., Cytotoxic diarylheptanoid induces cell cycle arrest and apoptosis via increasing ATF3 and stabilizing p53 in SH-SY5Y cells. Cancer Chemother Pharmacol, 2009. 63(6): p. 1131-9. 46. Huang, X., X. Li, and B. Guo, KLF6 induces apoptosis in prostate cancer cells through up-regulation of ATF3. J Biol Chem, 2008. 283(44): p. 29795-801. 47. Turchi, L., et al., Hif-2alpha mediates UV-induced apoptosis through a novel ATF3-dependent death pathway. Cell Death Differ, 2008. 15(9): p. 1472-80. 48. Nobori, K., et al., ATF3 inhibits doxorubicin-induced apoptosis in cardiac myocytes: a novel cardioprotective role of ATF3. J Mol Cell Cardiol, 2002. 34(10): p. 1387-97. 49. Cai, Y., et al., Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of c-Jun NH(2)-terminal kinase and promoter response element. Blood, 2000. 96(6): p. 2140-8. 50. Chaveroux, C., et al., Identification of a novel amino acid response pathway triggering ATF2 phosphorylation in mammals. Mol Cell Biol, 2009. 29(24): p. 6515-26. 51. Xie, J. and M.S. Roberson, 3'', 5''-cyclic adenosine 5''-monophosphate response element-dependent transcriptional regulation of the secretogranin II gene promoter depends on gonadotropin-releasing hormone-induced mitogen-activated protein kinase activation and the transactivator activating transcription factor 3. Endocrinology, 2008. 149(2): p. 783-92. 52. Jin, M.H., et al., Enhanced TGF-beta1 is involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced oxidative stress in C57BL/6 mouse testis. Toxicol Lett, 2008. 178(3): p. 202-9. 53. Chen, S.C., et al., Acute hypoxia to endothelial cells induces activating transcription factor 3 (ATF3) expression that is mediated via nitric oxide. Atherosclerosis, 2008. 201(2): p. 281-8. 54. Lu, D., J. Chen, and T. Hai, The regulation of ATF3 gene expression by mitogen-activated protein kinases. Biochem J, 2007. 401(2): p. 559-67. 55. Joo, J.H., et al., Farnesol-induced apoptosis in human lung carcinoma cells is coupled to the endoplasmic reticulum stress response. Cancer Res, 2007. 67(16): p. 7929-36. 56. Lim, J.H., et al., Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells. Diabetologia, 2006. 49(8): p. 1924-36. 57. Inoue, K., et al., TNFalpha-induced ATF3 expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells. Genes Cells, 2004. 9(1): p. 59-70. 58. Kool, J., et al., Induction of ATF3 by ionizing radiation is mediated via a signaling pathway that includes ATM, Nibrin1, stress-induced MAPkinases and ATF-2. Oncogene, 2003. 22(27): p. 4235-42. 59. Yu, R., et al., Adriamycin activates c-jun N-terminal kinase in human leukemia cells: a relevance to apoptosis. Cancer Lett, 1996. 107(1): p. 73-81. 60. Keith, R.J., et al., Aldose reductase decreases endoplasmic reticulum stress in ischemic hearts. Chem Biol Interact, 2009. 178(1-3): p. 242-9. 61. Haberzettl, P., et al., Role of endoplasmic reticulum stress in acrolein-induced endothelial activation. Toxicol Appl Pharmacol, 2009. 234(1): p. 14-24. 62. Lass, A., et al., Decreased ER-associated degradation of alpha-TCR induced by Grp78 depletion with the SubAB cytotoxin. Int J Biochem Cell Biol, 2008. 40(12): p. 2865-79. 63. Koh, E.H., et al., Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes, 2007. 56(12): p. 2973-81. 64. Sandnes, D., et al., Induction of LRF-1/ATF3 by vasopressin in hepatocytes: role of MAP kinases. Cell Physiol Biochem, 2010. 25(4-5): p. 523-32. 65. Hamdi, M., et al., ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses. DNA Repair (Amst), 2008. 7(3): p. 487-96. 66. Yang, H., et al., The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF-beta). Carcinogenesis, 2010. 31(4): p. 703-11. 67. Yaari-Stark, S., et al., Ras inhibits endoplasmic reticulum stress in human cancer cells with amplified Myc. Int J Cancer, 2010. 126(10): p. 2268-81. 68. Koh, I.U., et al., AdipoR2 is transcriptionally regulated by ER stress-inducible ATF3 in HepG2 human hepatocyte cells. FEBS J, 2010. 277(10): p. 2304-17. 69. Armstrong, J.L., et al., Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. J Biol Chem, 2010. 285(9): p. 6091-100. 70. Weidenfeld-Baranboim, K., et al., The ubiquitously expressed bZIP inhibitor, JDP2, suppresses the transcription of its homologue immediate early gene counterpart, ATF3. Nucleic Acids Res, 2009. 37(7): p. 2194-203. 71. Wang, Q., et al., ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc Natl Acad Sci U S A, 2009. 106(7): p. 2200-5. 72. Wek, R.C., H.Y. Jiang, and T.G. Anthony, Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans, 2006. 34(Pt 1): p. 7-11. 73. Tamura, K., et al., Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation. EMBO J, 2005. 24(14): p. 2590-601. 74. Perez-Tomas, R. and M. Vinas, New Insights on the Antitumoral Properties of Prodiginines. Curr Med Chem, 2010. 75. Montaner, B. and R. Perez-Tomas, The prodigiosins: a new family of anticancer drugs. Curr Cancer Drug Targets, 2003. 3(1): p. 57-65. 76. Llagostera, E., et al., Prodigiosin induces apoptosis by acting on mitochondria in human lung cancer cells. Ann N Y Acad Sci, 2003. 1010: p. 178-81. 77. Montaner, B. and R. Perez-Tomas, The cytotoxic prodigiosin induces phosphorylation of p38-MAPK but not of SAPK/JNK. Toxicol Lett, 2002. 129(1-2): p. 93-8. 78. Montaner, B. and R. Perez-Tomas, Prodigiosin induces caspase-9 and caspase-8 activation and cytochrome C release in Jurkat T cells. Ann N Y Acad Sci, 2002. 973: p. 246-9. 79. Mungrue, I.N., et al., CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol, 2009. 182(1): p. 466-76. 80. Gjymishka, A., N. Su, and M.S. Kilberg, Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway. Biochem J, 2009. 417(3): p. 695-703. 81. Green, T.A., et al., Induction of activating transcription factors (ATFs) ATF2, ATF3, and ATF4 in the nucleus accumbens and their regulation of emotional behavior. J Neurosci, 2008. 28(9): p. 2025-32. 82. Fawcett, T.W., et al., Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J, 1999. 339 ( Pt 1): p. 135-41. 83. Kim, R., et al., Role of the unfolded protein response in cell death. Apoptosis, 2006. 11(1): p. 5-13. 84. Lee, S.H., C. Krisanapun, and S.J. Baek, NSAID-activated gene-1 as a molecular target for capsaicin-induced apoptosis through a novel molecular mechanism involving GSK3beta, C/EBPbeta and ATF3. Carcinogenesis, 2010. 31(4): p. 719-28. 85. Piyanuch, R., et al., Berberine, a natural isoquinoline alkaloid, induces NAG-1 and ATF3 expression in human colorectal cancer cells. Cancer Lett, 2007. 258(2): p. 230-40. 86. Lee, S.H., et al., Indole-3-carbinol and 3,3''-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem Biophys Res Commun, 2005. 328(1): p. 63-9. 87. Bottone, F.G., Jr., et al., Gene modulation by Cox-1 and Cox-2 specific inhibitors in human colorectal carcinoma cancer cells. Carcinogenesis, 2004. 25(3): p. 349-57. 88. Yan, C. and D.D. Boyd, ATF3 regulates the stability of p53: a link to cancer. Cell Cycle, 2006. 5(9): p. 926-9. 89. Yan, C., et al., Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination. EMBO J, 2005. 24(13): p. 2425-35.
摘要: 在許多的研究中,Prodigiosin (PG) 已經被界定為一個有潛力的抗癌藥物。可是到目前為止,仍然不是很清楚 PG 能夠造成細胞走向細胞凋亡的確切標的。因此,也激發我們探討 PG 誘導細胞凋亡的機制。在經過了微陣列的篩選與分析後,我們發現 PG 能夠有效地提升癌細胞的 activating transcription factor 3 (ATF3) 基因表現量,因此,我們便著手進行相關的研究與探討。首先,我們看到了 PG 確實能夠誘導多種不同癌細胞之 ATF3 的大量表現,同時也找出這是經由調控啟動子的緣故。接著我們發現,c-Jun N-terminal kinase (JNK) 訊息傳遞路徑也參與了 ATF3 大量表現的調控,並且觀察到 endoplasmic reticulum (ER) stress 的情形產生。最後,當我們抑制 ATF3 的基因表現後,發現 PG 所誘導的細胞凋亡現象,有明顯被抑制的情形。綜合以上的研究結果,我們證實了 PG 能夠誘發癌細胞 ER stress 的情形產生,並且透過 ATF3 造成細胞凋亡,因此,ATF3 在 PG 所誘導的細胞凋亡中扮演了重要的角色,顯示 ATF3 是 PG 的一個新的分子標的。
Prodigiosin (PG) has been identified as a new and potential anti-cancer drug in a variety of studies. However, the precise targets of PG-induced apoptosis are still uncovered, and therefore identification of the target is the main focus in this study. By analyzing data from microarray, we found activating transcription factor 3 (ATF3) showed an obvious difference in expression. The results from quantitative real-time RT-PCR analysis and immunoblot analysis on a number of different kinds of cancer cell lines indicated that ATF3 can be highly induced by PG. Further analysis revealed that PG can activate the human ATF3 promoter, and c-Jun N-terminal kinase (JNK) signaling pathway is involved in the up-regulation of ATF3 by PG. Additionally, PG treatment was shown to induce endoplasmic reticulum (ER) stress. Finally, PG-induced apoptosis was significantly reduced by silencing ATF3. Together, these data indicated that PG activates JNK signaling to up-regulates ATF3, which in turn contributes to the induction of apoptosis, partly through ER stress. In conclusion, ATF3 not only plays an important role in PG-induced apoptosis, but also acts a novel molecular taget of PG.
URI: http://hdl.handle.net/11455/20136
其他識別: U0005-1008201017181200
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-1008201017181200
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