Advertisement

Journal of Molecular Medicine

, Volume 90, Issue 3, pp 309–319 | Cite as

Glucocorticoid receptor antagonist sensitizes TRAIL-induced apoptosis in renal carcinoma cells through up-regulation of DR5 and down-regulation of c-FLIP(L) and Bcl-2

  • Kyoung-jin Min
  • Ji Hoon Jang
  • Jung Tae Lee
  • Kyeong Sook Choi
  • Taeg Kyu Kwon
Original Article

Abstract

RU486 (Mifepristone) has been known as antiprogesterone and antiglucocorticoid agent. RU486 is also used for treatment of several cancers, such as breast, ovarian, prostate, and glaucoma. Here, we investigated the effect of RU486 on TRAIL-induced apoptosis in human renal carcinoma Caki cells. Low dose of RU486 (30–50 μM) alone had no effect on apoptosis, but RU486 markedly sensitized Caki cells to TRAIL-induced apoptosis. We found that up-regulation of death receptor 5 (DR5; receptor for TRAIL ligand), and down-regulation of Bcl-2 and c-FLIP (caspase regulator) contributes to RU-486 induced TRAIL sensitization. Down-regulation of DR5 by siRNA also blocked RU486 induced TRAIL sensitization. Furthermore, overexpression of Bcl-1 or c-FLIP(L) inhibited the cell death induced by the combined treatment with RU486 and TRAIL. RU486 increased DR5 expression at the transcriptional levels through induction of CHOP expression. By contrast, RU486 did not sensitize normal human mesangial cells to TRAIL-mediated apoptosis. Effect of RU486 on TRAIL-induced cancer cell apoptosis was independent of glucocorticoid receptor and progesterone receptor. Taken together, RU486 enhances TRAIL-mediated apoptosis through down-regulation of Bcl-2 and c-FLIP(L) as well as CHOP-mediated DR5 up-regulation.

Keywords

RU486 TRAIL Death receptor c-FLIP(L) Bcl-2 

Notes

Acknowledgment

This work was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A100711).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Herrmann W, Wyss R, Riondel A, Philibert D, Teutsch G, Sakiz E, Baulieu EE (1982) The effects of an antiprogesterone steroid in women: interruption of the menstrual cycle and of early pregnancy. C R Seances Acad Sci III 294:933–938PubMedGoogle Scholar
  2. 2.
    Robbins A, Spitz IM (1996) Mifepristone: clinical pharmacology. Clin Obstet Gynecol 39:436–450PubMedCrossRefGoogle Scholar
  3. 3.
    Gagne D, Pons M, Philibert D (1985) RU 38486: a potent antiglucocorticoid in vitro and in vivo. J Steroid Biochem 23:247–251PubMedCrossRefGoogle Scholar
  4. 4.
    Jung-Testas I, Baulieu EE (1983) Inhibition of glucocorticosteroid action in cultured L-929 mouse fibroblasts by RU 486, a new anti-glucocorticosteroid of high affinity for the glucocorticosteroid receptor. Exp Cell Res 147:177–182PubMedCrossRefGoogle Scholar
  5. 5.
    Bardon S, Vignon F, Chalbos D, Rochefort H (1985) RU486, a progestin and glucocorticoid antagonist, inhibits the growth of breast cancer cells via the progesterone receptor. J Clin Endocrinol Metab 60:692–697PubMedCrossRefGoogle Scholar
  6. 6.
    Olson JJ, Beck DW, Schlechte JA, Loh PM (1987) Effect of the antiprogesterone RU-38486 on meningioma implanted into nude mice. J Neurosurg 66:584–587PubMedCrossRefGoogle Scholar
  7. 7.
    Rose FV, Barnea ER (1996) Response of human ovarian carcinoma cell lines to antiprogestin mifepristone. Oncogene 12:999–1003PubMedGoogle Scholar
  8. 8.
    Sartor O, Figg WD (1996) Mifepristone: antineoplastic studies. Clin Obstet Gynecol 39:498–505PubMedCrossRefGoogle Scholar
  9. 9.
    Kamradt MC, Mohideen N, Vaughan AT (2000) RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells. Gynecol Oncol 77:177–182PubMedCrossRefGoogle Scholar
  10. 10.
    Lecureur V, Fardel O, Guillouzo A (1994) The antiprogestatin drug RU 486 potentiates doxorubicin cytotoxicity in multidrug resistant cells through inhibition of P-glycoprotein function. FEBS Lett 355:187–191PubMedCrossRefGoogle Scholar
  11. 11.
    Eid MA, Lewis RW, Kumar MV (2002) Mifepristone pretreatment overcomes resistance of prostate cancer cells to tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL). Mol Cancer Ther 1:831–840PubMedGoogle Scholar
  12. 12.
    Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA et al (1995) Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3:673–682PubMedCrossRefGoogle Scholar
  13. 13.
    Kataoka T (2005) The caspase-8 modulator c-FLIP. Crit Rev Immunol 25:31–58PubMedCrossRefGoogle Scholar
  14. 14.
    Safa AR, Day TW, Wu CH (2008) Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Curr Cancer Drug Targets 8:37–46PubMedCrossRefGoogle Scholar
  15. 15.
    Jin Z, McDonald ER 3rd, Dicker DT, El-Deiry WS (2004) Deficient tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis. J Biol Chem 279:35829–35839PubMedCrossRefGoogle Scholar
  16. 16.
    Kelly MM, Hoel BD, Voelkel-Johnson C (2002) Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression. Cancer Biol Ther 1:520–527PubMedCrossRefGoogle Scholar
  17. 17.
    Ng CP, Zisman A, Bonavida B (2002) Synergy is achieved by complementation with Apo2L/TRAIL and actinomycin D in Apo2L/TRAIL-mediated apoptosis of prostate cancer cells: role of XIAP in resistance. Prostate 53:286–299PubMedCrossRefGoogle Scholar
  18. 18.
    Walczak H, Bouchon A, Stahl H, Krammer PH (2000) Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapy-resistant tumor cells. Cancer Res 60:3051–3057PubMedGoogle Scholar
  19. 19.
    Zhang Y, Zhang B (2008) TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5. Mol Cancer Res 6:1861–1871PubMedCrossRefGoogle Scholar
  20. 20.
    Fauvet R, Dufournet Etienne C, Poncelet C, Bringuier AF, Feldmann G, Darai E (2006) Effects of progesterone and anti-progestin (mifepristone) treatment on proliferation and apoptosis of the human ovarian cancer cell line, OVCAR-3. Oncol Rep 15:743–748PubMedGoogle Scholar
  21. 21.
    Zhang H, Lu JJ, Gao QZ, Zhang J (2006) Induction of apoptosis by mifepristone in androgen-independent prostate cancer cell lines in vitro. Zhonghua Wai Ke Za Zhi 44:382–385PubMedGoogle Scholar
  22. 22.
    Ruiz de Almodovar C, Ruiz-Ruiz C, Munoz-Pinedo C, Robledo G, Lopez-Rivas A (2001) The differential sensitivity of Bc1-2-overexpressing human breast tumor cells to TRAIL or doxorubicin-induced apoptosis is dependent on Bc1-2 protein levels. Oncogene 20:7128–7133PubMedCrossRefGoogle Scholar
  23. 23.
    Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM (1997) The receptor for the cytotoxic ligand TRAIL. Science 276:111–113PubMedCrossRefGoogle Scholar
  24. 24.
    Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA et al (1997) TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 16:5386–5397PubMedCrossRefGoogle Scholar
  25. 25.
    Yamaguchi H, Wang HG (2004) CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279:45495–45502PubMedCrossRefGoogle Scholar
  26. 26.
    Yoshida T, Shiraishi T, Nakata S, Horinaka M, Wakada M, Mizutani Y, Miki T, Sakai T (2005) Proteasome inhibitor MG132 induces death receptor 5 through CCAAT/enhancer-binding protein homologous protein. Cancer Res 65:5662–5667PubMedCrossRefGoogle Scholar
  27. 27.
    Petrella A, Ercolino SF, Festa M, Gentilella A, Tosco A, Conzen SD, Parente L (2006) Dexamethasone inhibits TRAIL-induced apoptosis of thyroid cancer cells via Bcl-xL induction. Eur J Cancer 42:3287–3293PubMedCrossRefGoogle Scholar
  28. 28.
    Mahajan DK, London SN (1997) Mifepristone (RU486): a review. Fertil Steril 68:967–976PubMedCrossRefGoogle Scholar
  29. 29.
    Bonelli RM (1992) Mifepristone (RU 486). Diskussionsforum Med Ethik XXXVIII–XLIIIGoogle Scholar
  30. 30.
    Goldberg JR, Plescia MG, Anastasio GD (1998) Mifepristone (RU 486): current knowledge and future prospects. Arch Fam Med 7:219–222PubMedCrossRefGoogle Scholar
  31. 31.
    Haak HR, de Keizer RJ, Hagenouw-Taal JC, van Seters AP, Vielvoye GJ, van Dulken H (1990) Successful mifepristone treatment of recurrent, inoperable meningioma. Lancet 336:124–125PubMedGoogle Scholar
  32. 32.
    Jurado R, Lopez-Flores A, Alvarez A, Garcia-Lopez P (2009) Cisplatin cytotoxicity is increased by mifepristone in cervical carcinoma: an in vitro and in vivo study. Oncol Rep 22:1237–1245PubMedGoogle Scholar
  33. 33.
    Huang J, Zhang Y, Huang Y, Zhang X, Xiao J (2010) Reversal effect of mifepristone on adriamycin resistance in human breast cancer cell line MCF-7/ADM in vitro and in vivo. Zhong Nan Da Xue Xue Bao Yi Xue Ban 35:576–583PubMedGoogle Scholar
  34. 34.
    Dioufa N, Kassi E, Papavassiliou AG, Kiaris H (2010) Atypical induction of the unfolded protein response by mifepristone. Endocrine 38:167–173PubMedCrossRefGoogle Scholar
  35. 35.
    Lee JT, Lee TJ, Park JW, Kwon TK (2009) Se-methylselenocysteine sensitized TRAIL-mediated apoptosis via down-regulation of Bcl-2 expression. Int J Oncol 34:1455–1460PubMedGoogle Scholar
  36. 36.
    Um HJ, Oh JH, Kim YN, Choi YH, Kim SH, Park JW, Kwon TK (2010) The coffee diterpene kahweol sensitizes TRAIL-induced apoptosis in renal carcinoma Caki cells through down-regulation of Bcl-2 and c-FLIP. Chem Biol Interact 186:36–42PubMedCrossRefGoogle Scholar
  37. 37.
    Aurora AB, Biyashev D, Mirochnik Y, Zaichuk TA, Sanchez-Martinez C, Renault MA, Losordo D, Volpert OV (2010) NF-kappaB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement. Blood 116:475–484PubMedCrossRefGoogle Scholar
  38. 38.
    Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J (2001) NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol 21:5299–5305PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang X, Zhang L, Yang H, Huang X, Otu H, Libermann TA, DeWolf WC, Khosravi-Far R, Olumi AF (2007) c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer cells. Cancer Res 67:9425–9434PubMedCrossRefGoogle Scholar
  40. 40.
    Fukazawa T, Fujiwara T, Uno F, Teraishi F, Kadowaki Y, Itoshima T, Takata Y, Kagawa S, Roth JA, Tschopp J et al (2001) Accelerated degradation of cellular FLIP protein through the ubiquitin–proteasome pathway in p53-mediated apoptosis of human cancer cells. Oncogene 20:5225–5231PubMedCrossRefGoogle Scholar
  41. 41.
    Kaunisto A, Kochin V, Asaoka T, Mikhailov A, Poukkula M, Meinander A, Eriksson JE (2009) PKC-mediated phosphorylation regulates c-FLIP ubiquitylation and stability. Cell Death Differ 16:1215–1226PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Kyoung-jin Min
    • 1
  • Ji Hoon Jang
    • 1
  • Jung Tae Lee
    • 1
  • Kyeong Sook Choi
    • 2
  • Taeg Kyu Kwon
    • 1
  1. 1.Department of Immunology, School of MedicineKeimyung UniversityDaeguSouth Korea
  2. 2.Department of Molecular Science and Technology, Institute for Medical SciencesAjou University School of MedicineSuwonSouth Korea

Personalised recommendations