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Dioscin induces caspase-independent apoptosis through activation of apoptosis-inducing factor in breast cancer cells

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Abstract

Dioscin, a saponin extracted from the roots of Polygonatum zanlanscianense, shows several bioactivities such as antitumor, antifungal, and antiviral properties. Although, dioscin is already known to induce cell death in variety cancer cells, the molecular basis for dioscin-induced cell death was not definitely known in cancer cells. In this study, we found that dioscin treatment induced cell death in dose-dependent manner in breast cancer cells such as MDA-MB-231, MDA-MB-453, and T47D cells. Dioscin decreased expressions of Bcl-2 and cIAP-1 proteins, which were down-regulated at the transcriptional level. Conversely, Mcl-1 protein level was down-regulated by facilitating ubiquitin/proteasome-mediated Mcl-1 degradation in dioscin-treated cells. Pretreatment with z-VAD fails to attenuate dioscin-induced cell death as well as caspase-mediated events such as cleavages of procaspase-3 and PARP. In addition, dioscin treatment increased the population of annexin V positive cells and induced DNA fragmentation in a dose-dependent manner in MDA-MB-231 cells. Furthermore, apoptosis inducing factor (AIF) was released from the mitochondria and translocated to the nucleus. Suppression in AIF expression by siRNA reduced dioscin-induced apoptosis in MDA-MB-231 cells. Taken together, our results demonstrate that dioscin-induced cell death was mediated via AIF-facilitating caspase-independent pathway as well as down-regulating anti-apoptotic proteins such as Bcl-2, cIAP-1, and Mcl-1 in breast cancer cells.

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References

  1. van Gurp M, Festjens N, van Loo G, Saelens X, Vandenabeele P (2003) Mitochondrial intermembrane proteins in cell death. Biochem Biophys Res Commun 304(3):487–497

    Article  PubMed  Google Scholar 

  2. Fandy TE, Shankar S, Srivastava RK (2008) Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells. Mol Cancer 7:60

    Article  PubMed Central  PubMed  Google Scholar 

  3. Autret A, Martin SJ (2009) Emerging role for members of the Bcl-2 family in mitochondrial morphogenesis. Mol Cell 36(3):355–363

    Article  CAS  PubMed  Google Scholar 

  4. Thayyullathil F, Chathoth S, Hago A, Patel M, Galadari S (2008) Rapid reactive oxygen species (ROS) generation induced by curcumin leads to caspase-dependent and -independent apoptosis in L929 cells. Free Radic Biol Med 45(10):1403–1412

    Article  CAS  PubMed  Google Scholar 

  5. Li L, Chen GG, Lu YN, Liu Y, Wu KF, Gong XL, Gou ZP, Li MY, Liang NC (2012) Ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid inhibits growth of human lung cancer A549 cells by arresting cell cycle and triggering apoptosis. Chin J Cancer Res 24(2):109–115

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Pasupuleti N, Leon L, Carraway KL 3rd, Gorin F (2013) 5-Benzylglycinyl-amiloride kills proliferating and nonproliferating malignant glioma cells through caspase-independent necroptosis mediated by apoptosis-inducing factor. J Pharmacol Exp Ther 344(3):600–615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Seo KS, Kim H, Hong TH, Kim JS, Song KS, Yun EJ, Park JH, Jung YH, Park JI, Kweon GR, Yoon WH, Lim K, Hwang BD (2013) Apicularen A acetate induces cell death via AIF translocation and disrupts the microtubule network by down-regulating tubulin in HM7 human colon cancer cells. Biochem Biophys Res Commun 434(3):634–640

    Article  CAS  PubMed  Google Scholar 

  8. Soengas MS, Lowe SW (2003) Apoptosis and melanoma chemoresistance. Oncogene 22(20):3138–3151

    Article  CAS  PubMed  Google Scholar 

  9. Devarajan E, Sahin AA, Chen JS, Krishnamurthy RR, Aggarwal N, Brun AM, Sapino A, Zhang F, Sharma D, Yang XH, Tora AD, Mehta K (2002) Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene 21(57):8843–8851

    Article  CAS  PubMed  Google Scholar 

  10. McIlwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5(4):a008656

    Article  PubMed  Google Scholar 

  11. Sautour M, Mitaine-Offer AC, Miyamoto T, Dongmo A, Lacaille-Dubois MA (2004) A new steroidal saponin from Dioscorea cayenensis. Chem Pharm Bull (Tokyo) 52(11):1353–1355

    Article  CAS  Google Scholar 

  12. Wang Y, Che CM, Chiu JF, He QY (2007) Dioscin (saponin)-induced generation of reactive oxygen species through mitochondria dysfunction: a proteomic-based study. J Proteome Res 6(12):4703–4710

    Article  CAS  PubMed  Google Scholar 

  13. Kaskiw MJ, Tassotto ML, Mok M, Tokar SL, Pycko R, Th’ng J, Jiang ZH (2009) Structural analogues of diosgenyl saponins: synthesis and anticancer activity. Bioorg Med Chem 17(22):7670–7679

    Article  CAS  PubMed  Google Scholar 

  14. Lu B, Yin L, Xu L, Peng J (2011) Application of proteomic and bioinformatic techniques for studying the hepatoprotective effect of dioscin against CCl-induced liver damage in mice. Planta Med 77(5):407–415

    Article  CAS  PubMed  Google Scholar 

  15. Cai J, Liu M, Wang Z, Ju Y (2002) Apoptosis induced by dioscin in Hela cells. Biol Pharm Bull 25(2):193–196

    Article  CAS  PubMed  Google Scholar 

  16. Gao LL, Li FR, Jiao P, Yang MF, Zhou XJ, Si YH, Jiang WJ, Zheng TT (2011) Paris chinensis dioscin induces G2/M cell cycle arrest and apoptosis in human gastric cancer SGC-7901 cells. World J Gastroenterol 17(39):4389–4395

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Wang Z, Zhou J, Ju Y, Zhang H, Liu M, Li X (2001) Effects of two saponins extracted from the Polygonatum zanlanscianense pamp on the human leukemia (HL-60) cells. Biol Pharm Bull 24(2):159–162

    Article  CAS  PubMed  Google Scholar 

  18. Lv L, Zheng L, Dong D, Xu L, Yin L, Xu Y, Qi Y, Han X, Peng J (2013) Dioscin, a natural steroid saponin, induces apoptosis and DNA damage through reactive oxygen species: a potential new drug for treatment of glioblastoma multiforme. Food Chem Toxicol 59:657–669

    Article  CAS  PubMed  Google Scholar 

  19. Wang L, Meng Q, Wang C, Liu Q, Peng J, Huo X, Sun H, Ma X, Liu K (2013) Dioscin restores the activity of the anticancer agent adriamycin in multidrug-resistant human leukemia K562/adriamycin cells by down-regulating MDR1 via a mechanism involving NF-κB signaling inhibition. J Nat Prod 76(5):909–914

    Article  CAS  PubMed  Google Scholar 

  20. Ren SX, Shen J, Cheng AS, Lu L, Chan RL, Li ZJ, Wang XJ, Wong CC, Zhang L, Ng SS, Chan FL, Chan FK, Yu J, Sung JJ, Wu WK, Cho CH (2013) FK-16 derived from the anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells. PLoS ONE 8(5):e63641

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Qiao L, Wong BC (2009) Targeting apoptosis as an approach for gastrointestinal cancer therapy. Drug Resist Updat 12(3):55–64

    Article  CAS  PubMed  Google Scholar 

  22. Sun BT, Zheng LH, Bao YL, Yu CL, Wu Y, Meng XY, Li YX (2011) Reversal effect of Dioscin on multidrug resistance in human hepatoma HepG2/adriamycin cells. Eur J Pharmacol 654(2):129–134

    Article  CAS  PubMed  Google Scholar 

  23. Hu M, Xu L, Yin L, Qi Y, Li H, Xu Y, Han X, Peng J, Wan X (2013) Cytotoxicity of dioscin in human gastric carcinoma cells through death receptor and mitochondrial pathways. J Appl Toxicol 33(8):712–722

    Article  CAS  PubMed  Google Scholar 

  24. Candé C, Cecconi F, Dessen P, Kroemer G (2002) Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death? J Cell Sci 115(Pt 24):4727–4734

    Article  PubMed  Google Scholar 

  25. Pradelli LA, Bénéteau M, Ricci JE (2010) Mitochondrial control of caspase-dependent and -independent cell death. Cell Mol Life Sci 67(10):1589–1597

    Article  CAS  PubMed  Google Scholar 

  26. Kang YH, Yi MJ, Kim MJ, Park MT, Bae S, Kang CM, Cho CK, Park IC, Park MJ, Rhee CH, Hong SI, Chung HY, Lee YS, Lee SJ (2004) Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: reactive oxygen species-mediated poly(ADP-ribose) polymerase-1 activation signals apoptosis-inducing factor release from mitochondria. Cancer Res 64(24):8960–8967

    Article  CAS  PubMed  Google Scholar 

  27. Wang L, Liu L, Shi Y, Cao H, Chaturvedi R, Calcutt MW, Hu T, Ren X, Wilson KT, Polk DB, Yan F (2012) Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor. PLoS ONE 7(5):e36418

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Wang Z, Cheng Y, Wang N, Wang DM, Li YW, Han F, Shen JG, de Yang P, Guan XY, Chen JP (2012) Dioscin induces cancer cell apoptosis through elevated oxidative stress mediated by downregulation of peroxiredoxins. Cancer Biol Ther 13(3):138–147

    Article  CAS  PubMed  Google Scholar 

  29. Li L, Gao Y, Zhang L, Zeng J, He D, Sun Y (2008) Silibinin inhibits cell growth and induces apoptosis by caspase activation, down-regulating survivin and blocking EGFR-ERK activation in renal cell carcinoma. Cancer Lett 272(1):61–69

    Article  CAS  PubMed  Google Scholar 

  30. Spagnuolo C, Cerella C, Russo M, Chateauvieux S, Diederich M, Russo GL (2011) Quercetin downregulates Mcl-1 by acting on mRNA stability and protein degradation. Br J Cancer 105(2):221–230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Wu YL, Wan Y, Jin XJ, OuYang BQ, Bai T, Zhao YQ, Nan JX (2011) 25-OCH3-PPD induces the apoptosis of activated t-HSC/Cl-6 cells via c-FLIP-mediated NF-κB activation. Chem Biol Interact 194(2–3):106–112

    Article  CAS  PubMed  Google Scholar 

  32. Yu HY, Jin CY, Kim KS, Lee YC, Park SH, Kim GY, Kim WJ, Moon HI, Choi YH, Lee JH (2012) Oleifolioside A mediates caspase-independent human cervical carcinoma HeLa cell apoptosis involving nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG. J Agric Food Chem 60(21):5400–5406

    Article  CAS  PubMed  Google Scholar 

  33. Wei Y, Xu Y, Han X, Qi Y, Xu L, Xu Y, Yin L, Sun H, Liu K, Peng J (2013) Anti-cancer effects of dioscin on three kinds of human lung cancer cell lines through inducing DNA damage and activating mitochondrial signal pathway. Food Chem Toxicol 59:118–128

    Article  CAS  PubMed  Google Scholar 

  34. Kim YS, Kim EA, Park KG, Lee SJ, Kim MS, Sohn HY, Lee TJ (2012) Dioscin sensitizes cells to TRAIL-induced apoptosis through downregulation of c-FLIP and Bcl-2. Oncol Rep 28(5):1910–1916

    CAS  PubMed  Google Scholar 

  35. Hsieh MJ, Yang SF, Hsieh YS, Chen TY, Chiou HL (2012) Autophagy inhibition enhances apoptosis induced by dioscin in huh7 cells. Evid Based Complement Alternat Med 2012:134512

    PubMed Central  PubMed  Google Scholar 

  36. Hsieh MJ, Tsai TL, Hsieh YS, Wang CJ, Chiou HL (2013) Dioscin-induced autophagy mitigates cell apoptosis through modulation of PI3K/Akt and ERK and JNK signaling pathways in human lung cancer cell lines. Arch Toxicol 87(11):1927–1937

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2005-0049417).

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Authors and Affiliations

  1. Department of Anatomy, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong Nam-Gu, Daegu, 705-717, Korea

    Eun-Ae Kim, Ji-Hoon Jang, Eon-Gi Sung, In-Hwan Song, Joo-Young Kim & Tae-Jin Lee

  2. Department of Pharmacology, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong Nam-Gu, Daegu, 705-717, Korea

    Suji Kim

  3. Department of Food Science and Nutrition, Andong National University, Andong, 760-749, Korea

    Ho-Yong Sohn

  4. Department of Radiation Oncology, College of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, Korea

    Yun-Han Lee

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  1. Eun-Ae Kim
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Correspondence to Tae-Jin Lee.

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Kim, EA., Jang, JH., Lee, YH. et al. Dioscin induces caspase-independent apoptosis through activation of apoptosis-inducing factor in breast cancer cells. Apoptosis 19, 1165–1175 (2014). https://doi.org/10.1007/s10495-014-0994-z

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