Advertisement

Molecular and Cellular Biochemistry

, Volume 359, Issue 1–2, pp 33–43 | Cite as

Radicicol, an inhibitor of Hsp90, enhances TRAIL-induced apoptosis in human epithelial ovarian carcinoma cells by promoting activation of apoptosis-related proteins

  • Yun Jeong Kim
  • Seon Ae Lee
  • Soon Chul Myung
  • Wonyong Kim
  • Chung Soo Lee
Article

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various cancer cells. Hsp90 is known to be involved in cell survival and growth in tumor cells. Nevertheless, Hsp90 inhibitors exhibit a variable effect on the cytotoxicity of anticancer drugs. Furthermore, the combined effect of Hsp90 inhibitors on TRAIL-induced apoptosis in epithelial ovarian cancer cells has not been determined. To assess the ability of an inhibitor of Hsp90 inhibitor radicicol to promote apoptosis, we investigated the effect of radicicol on TRAIL-induced apoptosis in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. TRAIL induced a decrease in Bid, Bcl-2, Bcl-xL, and survivin protein levels, increase in Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9, and -3), cleavage of PARP-1 and an increase in the tumor suppressor p53 levels. Radicicol enhanced TRAIL-induced apoptosis-related protein activation, nuclear damage and cell death. These results suggest that radicicol may potentiate the apoptotic effect of TRAIL on ovarian carcinoma cell lines by increasing the activation of the caspase-8- and Bid-dependent pathway and the mitochondria-mediated apoptotic pathway, leading to caspase activation. Radicicol may confer a benefit in the TRAIL treatment of epithelial ovarian adenocarcinoma.

Keywords

TRAIL Radiciciol Epithelial ovarian adenocarcinoma cells Apoptosis-related proteins Promoting effect 

Notes

Acknowledgment

This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A085138).

References

  1. 1.
    Wu GS (2009) TRAIL as a target in anti-cancer therapy. Cancer Lett 285:1–5. doi: 10.1016/j.canlet.2009.02.029 PubMedCrossRefGoogle Scholar
  2. 2.
    Mahmood Z, Shukla Y (2010) Death receptors: targets for cancer therapy. Exp Cell Res 316:887–899. doi: 10.1016/j.excr.2009.12.011 PubMedCrossRefGoogle Scholar
  3. 3.
    Jin Z, El-Deiry WS (2005) Overview of cell death signaling pathways. Cancer Biol Ther 4:139–163PubMedCrossRefGoogle Scholar
  4. 4.
    Goetz MP, Toft DO, Ames MM, Erlichman C (2003) The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol 14:1169–1176. doi: 10.1093/annonc/mdg316 PubMedCrossRefGoogle Scholar
  5. 5.
    Mahalingam D, Swords R, Carew JS, Nawrocki ST, Bhalla K, Giles FJ (2009) Targeting HSP90 for cancer therapy. Br J Cancer 100:1523–1529. doi: 10.1038/sj.bjc.6605066 PubMedCrossRefGoogle Scholar
  6. 6.
    Young JC, Agashe VR, Siegers K, Harti FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5:781–791. doi: 10.1038/nrm1492 PubMedCrossRefGoogle Scholar
  7. 7.
    Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772. doi: 10.1038/nrc1716 PubMedCrossRefGoogle Scholar
  8. 8.
    Moser C, Lang SA, Stoeltzing O (2009) Heat-shock protein 90 (Hsp90) as a molecular target for therapy of gastrointestinal cancer. Anticancer Res 29:2031–2042PubMedGoogle Scholar
  9. 9.
    Reikvam H, Ersvaer E, Bruserud O (2009) Heat shock protein 90—a potential target in the treatment of human acute myelogenous leukemia. Curr Cancer Drug Targets 9:761–776PubMedCrossRefGoogle Scholar
  10. 10.
    Hwang M, Moretti L, Lu B (2009) HSP90 inhibitors: multi-targeted antitumor effects and novel combinatorial therapeutic approaches in cancer therapy. Curr Med Chem 16:3081–3092PubMedCrossRefGoogle Scholar
  11. 11.
    Fedier A, Stuedii A, Fink D (2005) Presence of MLH1 protein aggravates the potential of the HSP90 inhibitor radicicol to sensitize tumor cells to cisplatin. Int J Oncol 27:1697–1705PubMedGoogle Scholar
  12. 12.
    Ohba S, Hirose Y, Yoshida K, Yazaki T, Kawase T (2010) Inhibition of 90-kD heat shock protein potentiates the cytotoxicity of chemotherapeutic agents in human glioma cells. J Neurosurg 112:33–42. doi: 10.3171/2009.3.JNS081146 PubMedCrossRefGoogle Scholar
  13. 13.
    Powers MV, Workman P (2006) Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr Relat Cancer Suppl 1:S125–S135. doi: 10.1677/erc.1.01324 CrossRefGoogle Scholar
  14. 14.
    Sano M (2001) Radicicol and geldanamycin prevents neurotoxic effects of anti-cancer drugs on cultured embryonic sensory neurons. Neuropharmacology 40:947–953. doi: 10.1016/S0028-3908(01)00018-1 PubMedCrossRefGoogle Scholar
  15. 15.
    Sohn MJ, Noh HJ, Yoo ID, Kim WG (2007) Protective effect of radicicol against LPS/IFN-γ-induced neuronal cell death in rat cortical neuron-glia cultures. Life Sci 80:1706–1712. doi: 10.1016/j.lfs.2007.01.054 PubMedCrossRefGoogle Scholar
  16. 16.
    Högberg T, Glimelius B, Nygren P (2001) A systematic overview of chemotherapy effects in ovarian cancer. Acta Oncol 40:340–360PubMedCrossRefGoogle Scholar
  17. 17.
    Bookman MA (2003) Developmental chemotherapy and management of recurrent ovarian cancer. J Clin Oncol 21:149s–167s. doi: 10.1200/JCO.2003.02.553 PubMedCrossRefGoogle Scholar
  18. 18.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. doi: 10.1016/0022-1759(83)90303-4 PubMedCrossRefGoogle Scholar
  19. 19.
    Dai Y, Liu M, Tang W, Li Y, Lian J, Lawrence TS, Xu L (2009) A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-κB. BMC Cancer 9:392. doi: 10.1186/1471-2407-9-392 PubMedCrossRefGoogle Scholar
  20. 20.
    Huang S, Okumura K, Sinicrope FA (2009) BH3 mimetic obatoclax enhances TRAIL-mediated apoptosis in human pancreatic cancer cells. Clin Cancer Res 15:150–159. doi: 10.1158/1078-0432.CCR-08-1575 PubMedCrossRefGoogle Scholar
  21. 21.
    Andrisano V, Ballardini R, Hrelia P, Cameli N, Tosti A, Gotti R, Cavrini V (2001) Studies on the photostability and in vitro phototoxicity of labetalol. Eur J Pharm Sci 12:495–504. doi: 10.1016/S0928-0987(00)00218-9 PubMedCrossRefGoogle Scholar
  22. 22.
    Oberhammer FA, Pavelka M, Sharma S, Tiefenbacher R, Purchio AF, Bursch W, Schulte-Hermann R (1992) Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor β1. Proc Natl Acad Sci USA 89:5408–5412PubMedCrossRefGoogle Scholar
  23. 23.
    Wu H, Rao GN, Dai B, Singh P (2000) Autocrine gastrins in colon cancer cells up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-8. J Biol Chem 275:32491–32498. doi: 10.1074/jbc.M002458200 PubMedCrossRefGoogle Scholar
  24. 24.
    Berthier A, Lemaire-Ewing S, Prunet C, Monier S, Athias A, Bessede G, Pais de Barros JP, Laubriet A, Gambert P, Lizard G, Néel D (2004) Involvement of a calcium-dependent dephosphorylation of BAD associated with the localization of Trpc-1 within lipid rafts in 7-ketocholesterol-induced THP-1 cell apoptosis. Cell Death Differ 11:897–905. doi: 10.1038/sj.cdd.4401434 PubMedCrossRefGoogle Scholar
  25. 25.
    Chipuk JE, Green DR (2006) Dissecting p53-dependent apoptosis. Cell Death Differ 13:994–1002. doi: 10.1038/sj.cdd.4401908 PubMedCrossRefGoogle Scholar
  26. 26.
    Armstrong JS (2006) Mitochondria: a target for cancer therapy. Br J Pharmacol 147:239–248. doi: 10.1038/sj.bjp.0706556 PubMedCrossRefGoogle Scholar
  27. 27.
    Hu W, Kavanagh JJ (2003) Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 4:721–729. doi: 10.1016/S1470-2045(03)01277-4 PubMedCrossRefGoogle Scholar
  28. 28.
    MacFarlane M (2003) TRAIL-induced signaling and apoptosis. Toxicol Lett 139:89–97. doi: 10.1016/S0378-4274(02)00422-8 PubMedCrossRefGoogle Scholar
  29. 29.
    Czabotar PE, Colman PM, Huang DC (2009) Bax activation by Bim? Cell Death Differ 16:1187–1191. doi: 10.1038/cdd.2009.83 PubMedCrossRefGoogle Scholar
  30. 30.
    Camins A, Pallas M, Silvestre JS (2008) Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches. Methods Fin Exp Clin Pharmacol 30:43–65. doi: 10.1358/mf.2008.30.1.1090962 CrossRefGoogle Scholar
  31. 31.
    Kim R, Emi M, Tanabe K (2006) Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 57:545–553. doi: 10.1007/s00280-005-0111-7 PubMedCrossRefGoogle Scholar
  32. 32.
    Borutaite V (2010) Mitochondria as decision-makers in cell death. Environ Mol Mutagen 51:406–416. doi: 10.1002/em.20564 PubMedGoogle Scholar
  33. 33.
    Wiman KG (2006) Strategies for therapeutic targeting of the p53 pathway in cancer. Cell Death Differ 13:921–926. doi: 10.1038/sj.cdd.4401921 PubMedCrossRefGoogle Scholar
  34. 34.
    Chen F, Wang W, El-Deiry WS (2010) Current strategies to target p53 in cancer. Biochem Pharmacol 80:724–730. doi: 10.1016/j.bcp.2010.04.031 PubMedCrossRefGoogle Scholar
  35. 35.
    Zhivotovsky B, Orrenius S (2010) Cell death mechanisms: cross-talk and role in disease. Exp Cell Res 316:1374–1383. doi: 10.1016/j.yexcr.2010.02.037 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Yun Jeong Kim
    • 1
  • Seon Ae Lee
    • 1
  • Soon Chul Myung
    • 2
  • Wonyong Kim
    • 3
  • Chung Soo Lee
    • 1
  1. 1.Department of Pharmacology, College of MedicineChung-Ang UniversitySeoulSouth Korea
  2. 2.Department of UrologyChung-Ang University HospitalSeoulSouth Korea
  3. 3.Department of Microbiology, College of MedicineChung-Ang UniversitySeoulSouth Korea

Personalised recommendations