Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of SIRT1 Sensitizes TRAIL-Resistant MCF-7 Cells by Upregulation of DR5 and Inhibition of c-FLIP

SIRT1 억제에 의한 DR5 발현증강과 c-FLIP 발현저해 작용으로 사람유방암세포 MCF-7의 TRAIL 감수성 증강

  • Lee, Su-Hoon (Department of Biochemistry and Medical Research Institute, Pusan National University School of Medicine) ;
  • Kim, Hak-Bng (Department of Biochemistry and Medical Research Institute, Pusan National University School of Medicine) ;
  • Kim, Mi-Ju (Department of Biochemistry and Medical Research Institute, Pusan National University School of Medicine) ;
  • Lee, Jae-Won (Department of Biochemistry and Medical Research Institute, Pusan National University School of Medicine) ;
  • Bae, Jae-Ho (Department of Biochemistry and Medical Research Institute, Pusan National University School of Medicine) ;
  • Kim, Dong-Wan (Department of Microbiology, College of Natural Sciences, Changwon National University) ;
  • Kang, Chi-Dug (Department of Biochemistry and Medical Research Institute, Pusan National University School of Medicine) ;
  • Kim, Sun-Hee (Department of Biochemistry and Medical Research Institute, Pusan National University School of Medicine)
  • 이수훈 (부산대학교 의학전문대학원 생화학교실) ;
  • 김학봉 (부산대학교 의학전문대학원 생화학교실) ;
  • 김미주 (부산대학교 의학전문대학원 생화학교실) ;
  • 이재원 (부산대학교 의학전문대학원 생화학교실) ;
  • 배재호 (부산대학교 의학전문대학원 생화학교실) ;
  • 김동완 (창원대학교 자연과학대 미생물학과) ;
  • 강치덕 (부산대학교 의학전문대학원 생화학교실) ;
  • 김선희 (부산대학교 의학전문대학원 생화학교실)
  • Received : 2012.05.29
  • Accepted : 2012.09.05
  • Published : 2012.10.30
Download PDF
⟨ Previous Next ⟩

Abstract

The tumor necrosis, factor-related, apoptosis-inducing ligand (TRAIL) is regarded as a potentially useful anticancer agent with excellent selectivity for cancer cells. However, a considerable number of cancer cells are resistant to apoptosis induction by TRAIL. Developing strategies to overcome this resistance are important for the successful use of TRAIL for cancer therapy. Here, we revealed that siRNA-mediated downregulation of SIRT1 or SIRT1 inhibitor Amurensin G upregulated DR5 and c-Myc and downregulated c-$FLIP_{L/S}$ and Mcl-1, which was associated with sensitization of TRAIL-resistant MCF-7 cells to TRAIL. This result was followed by the activation of caspases, PARP cleavage, and downregulation of Bcl-2 in both TRAIL-treated MCF-7 cells transfected with SIRT1 siRNA and cells co-treated with Amurensin G and TRAIL. Our results suggest that the induction of DR5 and downregulation of c-FLIP via suppression of SIRT1 expression may be a useful strategy to increase the susceptibility of TRAIL-resistant cancer cells to TRAIL-induced cell death.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)은 암세포 선택적으로 작용하므로서 유용한 항암제로 주목 받고 있다. 그러나, TRAIL 에 내성을 나타내는 암세포도 많이 존재한다. 그러므로 TRAIL 내성을 극복할 수 있는 방법을 고안하는 연구는 암 치료 요법에 매우 중요하다. 본 연구에서는 SIRT1 siRNA 또는 SIRT1 inhibitor인 amurensin G를 사람 유방암세포에 처리하면 DR5및 c-Myc의 발현 증강과 c-$FLIP_{L/S}$ 및 Mcl-1 발현 억제를 유도하므로서, TRAIL 에 내성을 나타내는 사람유방암세포 MCF-7 세포의 TRAIL 감수성을 증강시킴을 알 수 있었다. 또한, SIRT1 억제에 의한 caspase 활성화, PARP cleavage 및 Bcl-2 발현감소를 나타내었다. 이러한 연구결과는 SIRT1 저해에 의한 DR5 유도와 함께 c-FLIP 발현 억제가 TRAIL 내성 암세포의 TRAIL 반응성 증강에 유용한 기전으로 사용 될 수 있음을 시사하였다.

Keywords

References

  1. Aron, J. L., Parthun, M. R., Marcucci, G., Kitada, S., Mone, A. P., Davis, M. E., Shen, T., Murphy, T., Wickham, J., Kanakry, C., Lucas, D. M., Reed, J. C., Grever, M. R. and Byrd, J. C. 2003. Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. Blood 102, 652-658. https://doi.org/10.1182/blood-2002-12-3794
  2. Ashkenazi, A., Pai, R. C., Fong, S., Leung, S., Lawrence, D. A., Marsters, S. A., Blackie, C., Chang, L., McMurtrey, A. E., Hebert, A., DeForge, L., Koumenis, I. L., Lewis, D., Harris, L., Bussiere, J., Koeppen, H., Shahrokh, Z. and Schwall, R. H. 1999. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155-162. https://doi.org/10.1172/JCI6926
  3. Bevis, K. S., Buchsbaum, D. J. and Straughn, J. M., Jr. 2010. Overcoming TRAIL resistance in ovarian carcinoma. Gynecol. Oncol. 119, 157-163. https://doi.org/10.1016/j.ygyno.2010.05.034
  4. Bhalla, K. N. 2005. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J. Clin. Oncol. 23, 3971-3993. https://doi.org/10.1200/JCO.2005.16.600
  5. Bolden, J. E., Peart, M. J. and Johnstone, R. W. 2006. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769-784. https://doi.org/10.1038/nrd2133
  6. Camphausen, K., Scott, T., Sproull, M. and Tofilon, P. J. 2004. Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation. Clin. Cancer Res. 10, 6066-6071. https://doi.org/10.1158/1078-0432.CCR-04-0537
  7. Carew, J. S., Giles, F. J. and Nawrocki, S. T. 2008. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 269, 7-17. https://doi.org/10.1016/j.canlet.2008.03.037
  8. Fulda, S. 2008. Modulation of TRAIL-induced apoptosis by HDAC inhibitors. Curr. Cancer Drug Targets 8, 132-140. https://doi.org/10.2174/156800908783769355
  9. Hall, M. A. and Cleveland, J. L. 2007. Clearing the TRAIL for Cancer Therapy. Cancer Cell 12, 4-6. https://doi.org/10.1016/j.ccr.2007.06.011
  10. Hernandez, A., Thomas, R., Smith, F., Sandberg, J., Kim, S., Chung, D. H. and Evers, B. M. 2001. Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis. Surgery 130, 265-272. https://doi.org/10.1067/msy.2001.115897
  11. Kim, H. B., Kim, M. J., Kim, D. Y., Lee, J. W., Bae, J. H., Kim, D. W., Kang, C. D. and Kim, S. H. 2011. High susceptibility of metastatic cells derived from human prostate and colon cancer cells to TRAIL and sensitization of TRAIL-insensitive primary cells to TRAIL by 4,5-dimethoxy- 2-nitrobenzaldehyde. Mol. Cancer 10, 46. https://doi.org/10.1186/1476-4598-10-46
  12. Kim, M. S., Blake, M., Baek, J. H., Kohlhagen, G., Pommier, Y. and Carrier, F. 2003. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res. 63, 7291-7300.
  13. Kruyt, F. A. 2008. TRAIL and cancer therapy. Cancer Lett. 263, 14-25. https://doi.org/10.1016/j.canlet.2008.02.003
  14. Liu, N., Zhang, J., Zhang, J., Liu, S., Liu, Y. and Zheng, D. 2008. Erbin-regulated sensitivity of MCF-7 breast cancer cells to TRAIL via ErbB2/AKT/NF-kappaB pathway. J. Biochem. 143, 793-801.
  15. Mahajan, S., Dammai, V., Hsu, T. and Kraft, A. S. 2008. Hypoxia-inducible factor-2alpha regulates the expression of TRAIL receptor DR5 in renal cancer cells. Carcinogenesis 29, 1734-1741. https://doi.org/10.1093/carcin/bgn132
  16. Nieminen, A. I., Partanen, J. I., Hau, A. and Klefstrom, J. 2007. c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis. EMBO J. 26, 1055-1067. https://doi.org/10.1038/sj.emboj.7601551
  17. Oh, W. K., Cho, K. B., Hien, T. T., Kim, T. H., Kim, H. S., Dao, T. T., Han, H. K., Kwon, S. M., Ahn, S. G., Yoon, J. H., Kim, T. H., Kim, Y. G. and Kang, K. W. 2010. Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1. Mol. Pharmacol. 78, 855-864. https://doi.org/10.1124/mol.110.065961
  18. Olmos, Y., Brosens, J. J. and Lam, E. W. 2011. Interplay between SIRT proteins and tumour suppressor transcription factors in chemotherapeutic resistance of cancer. Drug Resist. Updat. 14, 35-44. https://doi.org/10.1016/j.drup.2010.12.001
  19. Park, S. J., Kim, M. J., Kim, H. B., Sohn, H. Y., Bae, J. H., Kang, C. D. and Kim, S. H. 2009. Trichostatin A sensitizes human ovarian cancer cells to TRAIL-induced apoptosis by down-regulation of c-FLIPL via inhibition of EGFR pathway. Biochem. Pharmacol. 77, 1328-1336. https://doi.org/10.1016/j.bcp.2008.12.027
  20. Pathil, A., Armeanu, S., Venturelli, S., Mascagni, P., Weiss, T. S., Gregor, M., Lauer, U. M. and Bitzer, M. 2006. HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology 43, 425-434. https://doi.org/10.1002/hep.21054
  21. Perego, P., Zuco, V., Gatti, L. and Zunino, F. 2012. Sensitization of tumor cells by targeting histone deacetylases. Biochem. Pharmacol. 83, 987-994. https://doi.org/10.1016/j.bcp.2011.11.010
  22. Ricci, M. S., Jin, Z., Dews, M., Yu, D., Thomas-Tikhonenko, A., Dicker, D. T. and El-Deiry, W. S. 2004. Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol. Cell Biol. 24, 8541-8555. https://doi.org/10.1128/MCB.24.19.8541-8555.2004
  23. Ricci, M. S., Kim, S. H., Ogi, K., Plastaras, J. P., Ling, J., Wang, W., Jin, Z., Liu, Y. Y., Dicker, D. T., Chiao, P. J., Flaherty, K. T., Smith, C. D. and El-Deiry, W. S. 2007. Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell 12, 66-80. https://doi.org/10.1016/j.ccr.2007.05.006
  24. Schuchmann, M., Schulze-Bergkamen, H., Fleischer, B., Schattenberg, J. M., Siebler, J., Weinmann, A., Teufel, A., Worns, M., Fischer, T., Strand, S., Lohse, A. W. and Galle, P. R. 2006. Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy. Oncol. Rep. 15, 227-230.
  25. Shankar, S. and Srivastava, R. K. 2004. Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. Drug Resist. Updat. 7, 139-156. https://doi.org/10.1016/j.drup.2004.03.002
  26. Sheridan, J. P., Marsters, S. A., Pitti, R. M., Gurney, A., Skubatch, M., Baldwin, D., Ramakrishnan, L., Gray, C. L., Baker, K., Wood, W. I., Goddard, A. D., Godowski, P. and Ashkenazi, A. 1997. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818-821. https://doi.org/10.1126/science.277.5327.818
  27. Shetty, S., Graham, B. A., Brown, J. G., Hu, X., Vegh-Yarema, N., Harding, G., Paul, J. T. and Gibson, S. B. 2005. Transcription factor NF-kappaB differentially regulates death receptor 5 expression involving histone deacetylase 1. Mol. Cell Biol. 25, 5404-5416. https://doi.org/10.1128/MCB.25.13.5404-5416.2005
  28. Singh, T. R., Shankar, S. and Srivastava, R. K. 2005. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24, 4609-4623. https://doi.org/10.1038/sj.onc.1208585
  29. Sonnemann, J., Gange, J., Kumar, K. S., Muller, C., Bader, P. and Beck, J. F. 2005. Histone deacetylase inhibitors interact synergistically with tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) to induce apoptosis in carcinoma cell lines. Invest. New Drugs 23, 99-109. https://doi.org/10.1007/s10637-005-5854-9
  30. Suliman, A., Lam, A., Datta, R and Srivastava, R. K. 2001. Intracellular mechanisms of TRAIL: apoptosis through mitochondrial- dependent and -independent pathways. Oncogene 20, 2122-2133. https://doi.org/10.1038/sj.onc.1204282
  31. Walczak, H., Miller, R. E., Ariail, K., Gliniak, B., Griffith, T. S., Kubin, M., Chin, W., Jones, J., Woodward, A., Le, T., Smith, C., Smolak, P., Goodwin, R. G., Rauch, C. T., Schuh, J. C. and Lynch, D. H. 1999. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat. Med. 5, 157-163. https://doi.org/10.1038/5517
  32. Wang, Y., Engels, I. H., Knee, D. A., Nasoff, M., Deveraux, Q. L. and Quon, K. C. 2004. Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell 5, 501-512. https://doi.org/10.1016/S1535-6108(04)00113-8
  33. Watanabe, K., Okamoto, K. and Yonehara, S. 2005. Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP. Cell Death Differ. 12, 10-18. https://doi.org/10.1038/sj.cdd.4401507
  34. Yuan, J., Minter-Dykhouse, K. and Lou, Z. 2009. A c-Myc-SIRT1 feedback loop regulates cell growth and transformation. J. Cell Biol. 185, 203-211. https://doi.org/10.1083/jcb.200809167
  35. Zhang, L. and Fang, B. 2005. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 12, 228-237. https://doi.org/10.1038/sj.cgt.7700792