Effect of Bee Venom Death Receptor Dependent Apoptosis and JAK2/STAT3 Pathway in the Ovarian Cancer

난소암에서 봉독이 세포자멸사와 JAK2/STAT3 Pathway의 억제에 미치는 영향

  • Ahn, Byeong-Joon (Dept. of Acupuncture & Moxibustion, College of Oriental Medicine, Kyungwon University) ;
  • Song, Ho-Sueb (Dept. of Acupuncture & Moxibustion, College of Oriental Medicine, Kyungwon University)
  • 안병준 (경원대학교 한의과대학 침구학교실) ;
  • 송호섭 (경원대학교 한의과대학 침구학교실)
  • Received : 2012.01.17
  • Accepted : 2012.02.06
  • Published : 2012.02.20

Abstract

목적 : 이 연구는 봉독이 사람의 난소암 세포인 SKOV3와 PA-1에서 death receptor의 발현을 높여 세포자멸사를 촉진함으로써 암세포의 성장을 억제하는지 밝히고자 하였다. 방법 : 난소암의 세포자멸사의 관찰에는 DAPI, TUNEL staining assay를 시행하였으며, 세포자멸사 조절 단백질의 변동 관찰에는 western blot analysis를 시행하였고, 난소암 세포에서 death receptor의 변화를 관찰하기 위해 RT-PCR analysis를 시행하였다. 결과 : 1. DAPI, TUNEL staining assay 결과, 봉독은 투여량에 따라 세포자멸사의 유도를 통해 SKOV3와 PA-1 난소암세포의 증식을 억제하였고, 세포자멸사와 동반하여 DR4와 DR6의 발현이 두 암세포 모두에서 증가하였고, DR3의 출현은 PA-1 세포에서 증가하였다. 2. Death Receptor의 발현 증가에 따라 caspase-3, 8, 9 and Bax를 포함하는 세포자멸사 촉진 단백질의 발현이 동반하여 상승하였고 JAK2, STAT3의 인산화와 Bcl-2의 발현은 억제되었다. 3. siRNA 처리 시 봉독에 의한 DR3, DR4, DR6 발현증가와 STAT3의 활성억제가 역전되었다. 결론 : 이러한 결과는 봉독이 난소암 세포에서 DR3, DR4, DR6의 증가와 JAK2/STAT3 pathway의 억제를 통하여 세포자멸사를 유발한다는 것을 시사하며, 난소암의 예방과 치료에 효과적으로 활용될 수 있을 것으로 기대된다.

Keywords

References

  1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics. CA Cancer J Clin. 2003 ; 53(1) : 5-26. https://doi.org/10.3322/canjclin.53.1.5
  2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics. CA Cancer J Clin. 2005 ; 55(2) : 74-108. https://doi.org/10.3322/canjclin.55.2.74
  3. Ramirez I, Chon HS, Apte SM. The role of surgery in the management of epithelial ovarian cancer. Cancer Control. 2011 ; 18(1) : 22-30. https://doi.org/10.1177/107327481101800104
  4. Partridge EE, Barnes MN. Epithelial ovarian cancer: Prevention, diagnosis, and treatment. CA Cancer J Clin. 1999 ; 49(5) : 297-320. https://doi.org/10.3322/canjclin.49.5.297
  5. Jain A, Dubashi B, Reddy KS, Jain P. Weekly paclitaxel in ovarian cancer-the latest success story. Curr Oncol. 2011 ; 18(1) : 16-7
  6. Yoon J, Kim ES, Lee SJ, Park CW, Cha HJ, Hong BH, Choi KY. Apoptosis-related mRNA expression profiles of ovarian cancer cell lines following cisplatin treatment. J Gynecol Oncol. 2010 ; 21(4) : 255-61. https://doi.org/10.3802/jgo.2010.21.4.255
  7. O'Donovan TR, O'Sullivan GC, McKenna S. Induction of autophagy by drug-resistant eophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics. Autophagy 2011 ; 7(5) : 509-24. https://doi.org/10.4161/auto.7.5.15066
  8. Kang YJ, Kim IY, Kim EH, Yoon MJ, Kim SU, Kwon TK, Choi KS. Paxilline enhances TRAIL mediated apoptosis of glioma cells via modulation of c-FLIP, survivin and DR5. Exp Mol Med. 2011 ; 43(1) : 24-34. https://doi.org/10.3858/emm.2011.43.1.003
  9. Zhu DM, Shi J, Liu S, Liu Y, Zheng D. HIV infection enhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactive oxygen species. PLoS One. 2011 ; 6(4) : e18291. https://doi.org/10.1371/journal.pone.0018291
  10. Yoshida T, Horinaka M, Sakai T. "Combinationoriented molecular-targeting prevention" of cancer: a model involving the combination of TRAIL and a DR5 inducer. Environ Health Prev Med. 2010 ; 15(4) : 203-10. https://doi.org/10.1007/s12199-009-0128-3
  11. Inoue N, Matsuda F, Goto Y, Manabe N. Role of cell-death ligand-receptor system of granulosa cells in selective follicular atresia in porcine ovary. J Reprod Dev. 2011 ; 57(2) : 169-75. https://doi.org/10.1262/jrd.10-198E
  12. Ashkenazi A. Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev. 2008 ; 19(3-4) : 325-31. https://doi.org/10.1016/j.cytogfr.2008.04.001
  13. Elrod HA, Sun SY. Modulation of death receptors by cancer therapeutic agents. Cancer Biol Ther. 2008 ; 7(2) : 163-73. https://doi.org/10.4161/cbt.7.2.5335
  14. Sun SY. Understanding the role of the death receptor 5/FADD/caspase-8 death signaling in cancer metastasis. Mol Cell Pharmacol. 2011 ; 3(1) : 31-4.
  15. Shan XL, Zhou XY, Yang J, Wang YL, Deng YH, Zhang MX. Inhibitory effect and mechanism of cucurbitacin E on the proliferation of ovarian cancer cells and its mechanism. Chin J cancer. 2010 ; 29(1) : 20-4. https://doi.org/10.5732/cjc.009.10223
  16. Alvarez JV, Febbo PG, Ramaswamy S, Loda M, Richardson A, Frank DA. Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. Cancer Res. 2005 ; 65(12) : 5054-62. https://doi.org/10.1158/0008-5472.CAN-04-4281
  17. Deng JY, Sun D, Liu XY, Pan Y, Liang H. STAT-3 correlates with lymph node metastasis and cell survival in gastric cancer. World J Gastroenterol. 2010 ; 16(42) : 5380-7. https://doi.org/10.3748/wjg.v16.i42.5380
  18. Chen KF, Tai WT, Huang JW, Hsu CY, Chen WL, Cheng AL, Chen PJ, Shiau CW. Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf. Eur J Med Chem. 2011 ; 46(7) : 2845-51. https://doi.org/10.1016/j.ejmech.2011.04.007
  19. Park HJ, Lee SH, Son DJ, Oh KW, Kim KH, Song HS, Kim GJ, Oh GT, Yoon DY, Hong JT. Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit. Arthritis Rheum. 2004 ; 50(11) : 3504-15. https://doi.org/10.1002/art.20626
  20. Park JH, Jeong YJ, Park KK, Cho HJ, Chung IK, Min KS, Kim M, Lee KG, Yeo JH, Park KK, Chang YC. Melittin suppresses PMAinduced tumor cell invasion by inhibiting NFkappa B and AP-1-dependent MMP-9 expression. Mol Cells. 2010a ; 29(2) : 209-15. https://doi.org/10.1007/s10059-010-0028-9
  21. Park MH, Choi MS, Kwak DH, Oh KW, Yoon DY, Han SB, Song HS, Song MJ, Hong JT. Anti-cancer effect of bee venom in prostate cancer cells through activation of caspase path0 way via inactivation of NF-${\kappa}B$. Prostate. 2010b ; 61 : 801-12.
  22. Liu S, Yu M, He Y, Xiao L, Wang F, Song C, Sun S, Ling C, Xu Z. Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatology. 2008 ; 47 (6) : 1964-73. https://doi.org/10.1002/hep.22240
  23. Jang MH, Shin MC, Lim S, Han SM, Park HJ, Shin I, Lee JS, Kim KA, Kim EH, Kim CJ. Bee venom induces apoptosis and inhibits expression of cyclooxygenase-2 mRNA in human lung cancer cell line NCI-H1299. J Pharmacol Sci. 2003 ; 91(2) : 95-104. https://doi.org/10.1254/jphs.91.95
  24. Wang C, Chen T, Zhang N, Yang M, Li B, Lü X, Cao X, Ling C. Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/ p38 and inhibiting $I{\kappa}B{\alpha}$ kinase -$NF{\kappa}B$. J Biol Chem. 2009 ; 284(6) : 3804-13. https://doi.org/10.1074/jbc.M807191200
  25. Li J, Yu W, Tiwary R, Park SK, Xiong A, Sanders BG, Kline K. ${\alpha}$-TEA-induced death receptor dependent apoptosis involves activation of acid sphingomyelinase and elevated ceramideenriched cell surface membranes. Cancer Cell Int. 2010;10:40. https://doi.org/10.1186/1475-2867-10-40
  26. Zhu H, Liu XW, Ding WJ, Xu DQ, Zhao YC, Lu W, He QJ, Yang B. Up-regulation of death receptor 4 and 5 by celastrol enhances the anticancer activity of TRAIL/Apo-2L. Cancer Lett. 2010 ; 297(2) : 155-64. https://doi.org/10.1016/j.canlet.2010.04.030
  27. Kim EJ, Park SY, Lee JY, Park JH. Fucoidan present in brown algae induces apoptosis of human colon cancer cells. BMC Gastroenterol. 2010 ; 10 : 96. https://doi.org/10.1186/1471-230X-10-96
  28. Tang Y, Li X, Liu Z, Simoneau AR, Xie J, Zi X. Flavokawain B, a kava chalcone, induces apoptosis via up-regulation of death-receptor 5 and Bimexpression in androgen receptor negative, hormonal refractory prostate cancer cell lines and reduces tumor growth. Int J Cancer. 2010 ; 127(8) : 1758-68. https://doi.org/10.1002/ijc.25210
  29. Sun SY. Understanding the role of the death receptor 5/FADD/caspase-8 death signaling in cancer metastasis. Mol Cell Pharmacol. 2011 ; 3(1) : 31-4.
  30. Elrod HA, Sun SY. Modulation of death receptors by cancer therapeutic agents. Cancer Biol Ther. 2008 ; 7(2) : 163-73. https://doi.org/10.4161/cbt.7.2.5335
  31. Yang A, Wilson NS, Ashkenazi A. Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. Curr Opin Cell Biol. 2010 ; 22(6) : 837-44. https://doi.org/10.1016/j.ceb.2010.08.001
  32. Kim BH, Min YS, Choi JS, Baeg GH, Kim YS, Shin JW, Kim TY, Ye SK. Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling. Exp Mol Med. 2011 ; 43(5) : 313-21. https://doi.org/10.3858/emm.2011.43.5.035
  33. Thoennissen NH, Iwanski GB, Doan NB, Okamoto R, Lin P, Abbassi S, Song JH, Yin D, Toh M, Xie WD, Said JW, Koeffler HP. Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res. 2009 ; 69(14) : 5876-84. https://doi.org/10.1158/0008-5472.CAN-09-0536
  34. Colomiere M, Ward AC, Riley C, Trenerry MK, Cameron-Smith D, Findlay J, Ackland L, Ahmed N. Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomas. Br J Cancer. 2009 ; 100(1) : 134-44. https://doi.org/10.1038/sj.bjc.6604794
  35. Sun M, Liu C, Nadiminty N, Lou W, Zhu Y, Yang J, Evans CP, Zhou Q, Gao AC. Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. Prostate. 2011 ; 72(1) : 82-89.
  36. Saydmohammed M, Joseph D, Syed V. Curcumin suppresses constitutive activation of STAT-3 by up-regulating protein inhibitor of activated STAT-3 (PIAS-3) in ovarian and endometrial cancer cells. J Cell Biochem. 2010 ; 110(2) : 447-56.
  37. Efimova EV, Liang H, Pitroda SP, Labay E, Darga TE, Levina V, Lokshin A, Roizman B, Weichselbaum RR, Khodarev NN. Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling. Int J Radiat Biol. 2009 ; 85(5) : 421-31. https://doi.org/10.1080/09553000902838566
  38. Maduro JH, Noordhuis MG, ten Hoor KA, Pras E, Arts HJ, Eijsink JJ, Hollema H, Mom CH, de Jong S, de Vries EG, de Bock GH, van der Zee AG. The prognostic value of TRAIL and its death receptors in cervical cancer. Int J Radiat Oncol Biol Phys. 2009 ; 75(1) : 203-11. https://doi.org/10.1016/j.ijrobp.2009.03.071