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20(s)-ginsenoside Rg3 promotes apoptosis in human ovarian cancer HO-8910 cells through PI3K/Akt and XIAP pathways

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Tumor Biology

Abstract

Ovarian cancer is a serious tumor which represents a great threat to women’s health. Recently, researchers had found that 20(s)-ginsenoside Rg3 could inhibit growth of several cancer cell lines; however, the mechanism is not fully understood so far. In the present study, we found that 20(s)-ginsenoside Rg3 reduced cell viability and induced apoptosis in a dose- and time-dependent manner in the human ovarian cancer cells HO-8910. The induction of apoptosis was accompanied by downregulation of phosphatidylinositol 3-kinase (PI3K)/Akt family proteins and inhibitor of apoptosis protein (IAP) family proteins. 20(s)-ginsenoside Rg3 treatment resulted in activation of caspase-3 and -9, which may partly explain the anti-cancer activity of 20(s)-ginsenoside Rg3. Taken together, our study for the first time suggests that 20(s)-ginsenoside Rg3 is able to enhance apoptosis of HO-8910 cells, at least in part, through downregulation of PI3K/Akt and IAP family proteins. Moreover, the triggering of caspase-3 and -9 activation mediated apoptotic induction. Our data indicate that 20(s)-ginsenoside Rg3 is an effective apoptosis-inducing natural compound in ovarian cancer cells and may have a role in future therapies for ovarian cancer.

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References

  1. Fu WM, Zhang JF, Wang H, Tan HS, Wang WM, Chen SC, et al. Apoptosis induced by 1,3,6,7-tetrahydroxyxanthone in hepatocellular carcinoma and proteomic analysis. Apoptosis. 2012;17:842–51.

    Article  CAS  Google Scholar 

  2. Zhang QH, Wu CF, Duan L, Yang JY. Protective effects of 20(s)-ginsenoside Rg3 against cyclophosphamide-induced DNA damage and cell apoptosis in mice. Arch Toxicol. 2008;82:117–23.

    Article  CAS  Google Scholar 

  3. Kim BJ, Nah SY, Jeon JH, So I, Kim SJ. Transient receptor potential melastatin 7 channels are involved in 20(s)-ginsenoside Rg3-induced apoptosis in gastric cancer cells. Basic Clin Pharmacol Toxicol. 2011;109:233–9.

    Article  CAS  Google Scholar 

  4. Kim JH, Kwon SK, Sung NY, Jung PM, Choi JI, Kim JK, et al. Effect of gamma irradiation on the conversion of ginsenoside Rb1 to Rg3. Radiat Phys Chem. 2012;81:1128–31.

    Article  CAS  Google Scholar 

  5. Yang LQ, Wang B, Gan H, Fu ST, Zhu XX, Wu ZN, et al. Enhanced oral bioavailability and anti-tumour effect of paclitaxel by 20(s)-ginsenoside Rg3 in vivo. Biopharm Drug Dispos. 2012;33:425–36.

    Article  CAS  Google Scholar 

  6. Lu P, Su W, Miao ZH, Niu HR, Liu J, Hua QL. Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer. Chin J Integr Med. 2008;14:33–6.

    Article  CAS  Google Scholar 

  7. Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol. 1999;17:2941–53.

    Article  CAS  Google Scholar 

  8. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002;108:153–64.

    Article  CAS  Google Scholar 

  9. Szliszka E, Zydowicz G, Janoszka B, Dobosz C, Kowalczyk-Ziomek G, Krol W. Ethanolic extract of Brazilian green propolis sensitizes prostate cancer cells to TRAIL-induced apoptosis. Int J Oncol. 2011;38:941–53.

    CAS  PubMed  Google Scholar 

  10. Lee JY, Jung KH, Morgan MJ, Kang YR, Lee HS, Koo GB, et al. Sensitization of TRAIL-induced cell death by 20(S)-ginsenoside Rg3 via CHOP-mediated DR5 upregulation in human hepatocellular carcinoma cells. Mol Cancer Ther. 2013;12:274–85.

    Article  CAS  Google Scholar 

  11. Yuan HD, Quan HY, Zhang Y, Kim SH, Chung SH. 20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway. Mol Med Rep. 2010;3:825–31.

    CAS  PubMed  Google Scholar 

  12. Sin S, Kim SY, Kim SS. Chronic treatment with ginsenoside Rg3 induces Akt-dependent senescence in human glioma cells. Int J Oncol. 2012;41:1669–74.

    Article  CAS  Google Scholar 

  13. Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, et al. Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell. 2003;11:519–27.

    Article  CAS  Google Scholar 

  14. Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG. A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science. 2004;305:1471–4.

    Article  CAS  Google Scholar 

  15. Mielczarek-Palacz A, Kondera-Anasz Z, Sikora J. Higher serum levels of tumour necrosis factor and its soluble receptors are associated with ovarian tumours. Arch Med Sci. 2012;8:848–53.

    Article  CAS  Google Scholar 

  16. Goncharenko-Khaider N, Matte I, Lane D, Rancourt C, Piché A. Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis. Mol Cancer. 2012;11:84.

    Article  CAS  Google Scholar 

  17. Ali AY, Farrand L, Kim JY, Byun S, Suh JY, Lee HJ, et al. Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum. Ann N Y Acad Sci. 2012;1271:58–67.

    Article  CAS  Google Scholar 

  18. Shen Y, Ren M, Shi Y, Zhang Y, Cai Y. Octreotide enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin chemotherapy in vitro. Exp Ther Med. 2011;2:1171–6.

    Article  CAS  Google Scholar 

  19. Rasul A, Ding C, Li XM, Khan M, Yi F, Ali M, et al. Dracorhodin perchlorate inhibits PI3K/Akt and NF-κB activation, up-regulates the expression of p53, and enhances apoptosis. Apoptosis. 2012;17:1104–19.

    Article  CAS  Google Scholar 

  20. Cheng LQ, Na JR, Bang MH, Kim MK, Yang DC. Conversion of major ginsenoside Rb1 to 20(S)-ginsenoside Rg3 by Microbacterium sp. GS514. Phytochemistry. 2008;69:218–24.

    Article  CAS  Google Scholar 

  21. Park DW, Bae JH, Jeon J, Lee N, Oh G, Yang YH, et al. Immunopotentiation and antitumor effect of a 20(s)-ginsenoside Rg3-fortified red ginseng preparation in mice bearing H640 lung cancer cells. Environ Toxicol Pharmacol. 2011;31:397–405.

    Article  CAS  Google Scholar 

  22. Zhang C, Liu LJ, Yu Y, Chen B, Tang CW, Li X. Antitumor effects of ginsenoside Rg3 on human hepatocellular carcinoma cells. Mol Med Rep. 2011;5:1295–8.

    Google Scholar 

  23. Kar S, Palit S, Ball WB, Das PK. Carnosic acid modulates Akt/IKK/NF-κB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells. Apoptosis. 2012;17:735–47.

    Article  CAS  Google Scholar 

  24. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.

    Article  CAS  Google Scholar 

  25. Allard D, Figg N, Bennett MR, Littlewood TD. Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3. J Biol Chem. 2008;283:19739–47.

    Article  CAS  Google Scholar 

  26. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785–9.

    Article  CAS  Google Scholar 

  27. Kang S, Dong SM, Kim BR, Park MS, Trink B, Byun HJ, et al. Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis. 2012;17:989–97.

    Article  CAS  Google Scholar 

  28. Yin S, Dong Y, Li J, Fan L, Wang L, Lu J, et al. Methylseleninic acid potentiates multiple types of cancer cells to ABT-737-induced apoptosis by targeting Mcl-1 and Bad. Apoptosis. 2012;17:388–99.

    Article  CAS  Google Scholar 

  29. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009;15:1126–32.

    Article  CAS  Google Scholar 

  30. Malaguarnera L. Implications of apoptosis regulators in tumorigenesis. Cancer Metastasis Rev. 2004;23:367–87.

    Article  CAS  Google Scholar 

  31. Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG, et al. Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem. 2004;279:5405–12.

    Article  CAS  Google Scholar 

  32. Ahn KS, Sethi G, Aggarwal BB. Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic gene products. Mol Pharmacol. 2007;71:209–19.

    Article  CAS  Google Scholar 

  33. Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller PP, et al. Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem. 2004;47:2430–40.

    Article  CAS  Google Scholar 

  34. Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 2008;9:231–41.

    Article  CAS  Google Scholar 

  35. Paramasivam A, Sambantham S, Shabnam J, Raghunandhakumar S, Anandan B, Rajiv R, et al. Anti-cancer effects of thymoquinone in mouse neuroblastoma (Neuro-2a) cells through caspase-3 activation with down-regulation of XIAP. Toxicol Lett. 2012;213:151–9.

    Article  CAS  Google Scholar 

  36. Shi Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell. 2002;9:459–70.

    Article  CAS  Google Scholar 

  37. Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006;7:988–94.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81101224), Outstanding Scientific Fund of Shengjing Hospital (201206), Tackle Key Problems in Science and Technology of Liaoning Province (2011225020), and Tackle Key Problems in Science and Technology of Shenyang City (F12-193-9-20).

Author contributions

Conceived and designed the experiments: JHW and JFN. Performed the experiments: JHW, JFN, and PH. Analyzed the data: MZ and PH. Contributed reagents/materials/analysis tools: PH. Wrote the paper: JHW and JFN.

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Authors and Affiliations

  1. Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China

    Jia-He Wang, Meng Zhang & Ping He

  2. Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China

    Jian-Fei Nao

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  1. Jia-He Wang
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Correspondence to Jia-He Wang.

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Wang, JH., Nao, JF., Zhang, M. et al. 20(s)-ginsenoside Rg3 promotes apoptosis in human ovarian cancer HO-8910 cells through PI3K/Akt and XIAP pathways. Tumor Biol. 35, 11985–11994 (2014). https://doi.org/10.1007/s13277-014-2497-5

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  • DOI: https://doi.org/10.1007/s13277-014-2497-5

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