Influence of 17β-Estradiol on 15-Deoxy-Δ12,14 Prostaglandin J2 -Induced Apoptosis in MCF-7 and MDA-MB-231 Cells

  • Published : 2013.11.30


The nuclear receptor, peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$), is expressed in various cancer cells including breast, prostate, colorectal and cervical examples. An endogenous ligand of $PPAR{\gamma}$, 15-deoxy-${\Delta}^{12,14}$ prostaglandin $J_2$ (PGJ2), is emerging as a potent anticancer agent but the exact mechanism has not been fully elucidated, especially in breast cancer. The present study compared the anticancer effects of PGJ2 on estrogen receptor alpha ($ER{\alpha}$)-positive (MCF-7) and $ER{\alpha}$-negative (MDA-MB-231) human breast cancer cells. Based on the reported signalling cross-talk between $ER{\alpha}$ and $ER{\alpha}$, the effect of the $ER{\alpha}$ ligand, $17{\beta}$-estradiol (E2) on the anticancer activities of PGJ2 in both types of cells was also explored. Here we report that PGJ2 inhibited proliferation of both MCF-7 and MDA-MB-231 cells by inducing apoptotic cell death with active involvement of mitochondria. The presence of E2 potentiated PGJ2-induced apoptosis in MCF-7, but not in MDA-MB-231 cells. The $ER{\alpha}$ antagonist, GW9662, failed to block PGJ2-induced activities but potentiated its effects in MCF-7 cells, instead. Interestingly, GW9662 also proved capable of inducing apoptotic cell death. It can be concluded that E2 enhances $ER{\alpha}$-independent anticancer effects of PGJ2 in the presence of its receptor.


15 deoxy-prostaglandin $J_2$;$17{\beta}$-estradiol;apoptosis;MCF-7;MDA-MB-231;GW9662


  1. Nikitakis NG, Siavash H, Hebert C, et al (2002). 15d-PG$J_{2}$, but not thiazolidiones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells. Br J Cancer, 87, 1396-403.
  2. Qin C, Burghardt R, Smith R, et al (2003). Peroxisome proliferator-activated receptor gamma agonists induce proteasome-dependent degradation of cyclin D1 and estrogen receptor alpha in MCF-7 breast cancer cells. Cancer Res, 63, 958-64.
  3. Pignatelli M, Sanchez-Rodriguez J, Santos A, Perez-Castillo A (2005). 15-Deoxy-D-12,14-prostaglandin $J_{2}$ induces programmed cell death of breast cancer cells by a pleiotropic mechanism. Carcinogenesis, 26, 81-92.
  4. Ray DM, Akbiyik F, Phipps RP (2006). The peroxisome proliferator activated receptor gamma (PPARgamma) ligands 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARgamma-independent mechanisms. J Immunol, 177, 5068-76.
  5. Seargent AM, Yates EA, Hill JH (2004). GW9662, a potent antagonist of PPAR$\gamma$, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPAR$\gamma$ agonist rosiglitazone, independently of PPAR$\gamma$ activation. Br J Pharmacol, 143, 933-7.
  6. Song RX, Mor G, Naftolin F, et al (2001). Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17$\beta$-estradiol. J Natl Cancer Inst, 93, 1714-23.
  7. Theoleyre S, Mottier S, Masson D, Denis MG (2010). HtrA3 is regulated by 15-deoxy Delta12, 14-prostaglandin J2 independently of PPARgamma in clear cell renal cell carcinomas. Biochem Biophys Res Commun, 394, 453-8.
  8. Wang X, Kilgore MW (2002). Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells. Mol Cell Endocrinol, 194, 123-33.
  9. Wei S, Yang J, Lee SL, Kulp SK, Chen CS (2009). PPARgamma-independent antitumor effects of thiazolidinediones. Cancer Lett, 276, 119-24.
  10. Lecomte J, Flament S, Salamone S, et al (2008). Disruption of ER$\alpha$ signaling pathway by PPARgamma agonists: evidences of PPARgamma-independent events in two hormone-dependent breast cancer cell lines. Breast Cancer Res Treat, 112, 437-51.
  11. Lee YR, Park J, Yu HN, et al (2005). Up-regulation of PI3K/Akt signaling by 17$\beta$-estradiol through activation of estrogen receptor-$\alpha$, but not estrogen receptor-$\beta$, and stimulates cell growth in breast cancer cells. Biochem Biophys Res Commun, 336, 1221-6.
  12. Lee HJ, Ju J, Paul S, et al (2009). Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma. Clin Cancer Res, 15, 4242-9.
  13. Lee MT, Leung YK, Chung I, Tarapore P, Ho SM (2013). Estrogen receptor $\beta$ (ER$\beta$1) transactivation is differentially modulated by the transcriptional coregulator Tip60 in a cis-acting element-dependent manner. J Biol Chem, 288, 25038-52.
  14. Leesnitzer LM, Parks DJ, Bledsoe RK, et al (2002). Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry, 41, 6640-50.
  15. Malaviya A, Sylvester PW (2013). Mechanisms mediating the effects of $\gamma$-tocotrienol when used in combination with PPAR$\gamma$ agonists or antagonists on MCF-7 and MDA-MB-231 breast cancer cells. Int J Breast Cancer, [Epub ahead of print].
  16. Mukherjee R, Jow L, Croston GE, Paterniti JR (1997). Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPAR$\gamma$2 versus PPAR$\gamma$1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem, 272, 8071-6.
  17. Apostoli AJ, Skelhorne-Gross GE, Rubino RE, et al (2013). Loss of PPAR$\gamma$ expression in mammary secretory epithelial cells creates a pro-breast tumourigenic environment. Int J Cancer, [Epub ahead of print].
  18. Bailey DB, Hla T (1999). Endothelial cell apoptosis induced by peroxisome proliferator-activated receptor ligand 15d-PG$J_{2}$. J Biol Chem, 274, 17042-8.
  19. Bonofiglio D, Gabriele S, Aquila S, et al (2005). Estrogen receptor binds to peroxisome proliferator.activated receptor response element and negatively interferes with peroxisome proliferator.activated receptor signaling in breast cancer cells. Clin Cancer Res, 11, 6139-47.
  20. Chang SS, Hu HY (2013). Association of thiazolidinediones with gastric cancer in type 2 diabetes mellitus: a population-based case--control study. BMC Cancer, 13, 420.
  21. Chbicheb S, Yao X, Rodeau JL, et al (2011). EGR1 expression: a calcium and ERK1/2 mediated PPAR$\gamma$-independent event involved in the antiproliferative effect of 15-deoxy-$\Delta^{12,14}$-prostaglandin J2 and thiazolidinediones in breast cancer cells. Biochem Pharmacol, 81, 1087-97.
  22. Choi IK, Kim YH, Kim J, Seo JH (2008). PPAR-$\gamma$ ligand promotes the growth of APC-mutated HT-29 human colon cancer cells in vitro and in vivo. Invest New Drugs, 26, 283-8.
  23. Clay CE, Namen AM, Atsumi G, et al (1999). Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells. Carcinogenesis, 20, 1905-11.
  24. Clay CE, Namen AM, Fonteh A, et al (2000). 15-Deoxy-delta(12, 14) PGJ(2) induces diverse biological responses via PPARgamma activation in cancer cells. Prostaglandins Other Lipid Mediat, 62, 23-32.
  25. Clay CE, Monjazeb A, Thorburn J, Chilton FH, High KP (2002). 15-Deoxy-delta12,14-prostaglandin $J_{2}$-induced apoptosis does not require PPARgamma in breast cancer cells. J Lipid Res, 43, 1818-28.
  26. Ferreira-Silva V, Rodrigues AC, Hirata TDC, Hirabara SM, Curi R (2008). Effects of 15-deoxy-$\Delta^{12,14}$ prostaglandin $J_{2}$ and ciglitazone on human cancer cell cycle progression and death: the role of PPAR gamma. Eur J Pharmacol, 580, 80-6.
  27. Gregoraszczuk E, Ptak A (2011). Involvement of caspase-9 but not caspase-8 in the anti-apoptotic effects of estradiol and 4-OH-Estradiol in MCF-7 human breast cancer cells. Endocr Regul, 45, 3-8.
  28. Gupta PB, Kuperwasser C (2006). Contributions of estrogen to ER-negative breast tumor growth. J Steroid Biochem Mol Biol, 102, 71-8.
  29. Houston KD, Copland JA, Broaddus RR, et al (2003). Inhibition of proliferation and estrogen receptor signaling by peroxisome proliferator-activated receptor $\gamma$ ligands in uterine leiomyoma. Cancer Res, 63, 1221-7.
  30. Jeong S, Yoon M (2011). 17$\beta$-Estradiol inhibition of PPAR$\gamma$-induced adipogenesis and adipocyte-specific gene expression. Acta Pharmacol Sin, 32, 230-8.
  31. Kamagata C, Tsuji N, Moriai M, Kobayashi D, Watanabe N (2007). 15-Deoxy-D12, 14-prostaglandin $J_{2}$ inhibits G2-M phase progression in human breast cancer cells via the down-regulation of cyclin B1 and survivin expression. Breast Cancer Res Treat, 102, 263-73.
  32. Keller H, Givel F, Perroud M, Wahli W (1995). Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements. Mol Endocrinol, 19, 794-804.
  33. Kim HJ, Kim JY, Meng Z, et al (2007). 15-deoxy-Delta12, 14-prostaglandin $J_{2}$ inhibits transcriptional activity of estrogen receptor-alpha via covalent modification of DNA-binding domain. Cancer Res, 67, 2595-602.
  34. Kim EH, Na HK, Kim DH, et al (2008). 15-Deoxy-D12,14-prostaglandin $J_{2}$ induces COX-2 expression through Akt-driven AP-1 activation in human breast cancer cells: a potential role of ROS. Carcinogenesis, 29, 688-95.
  35. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM (1992). Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature, 358, 771-4.
  36. Kourtidis A, Srinivasaiah R, Carkner RD, Brosnan MJ, Conklin DS (2009). Peroxisome proliferator-activated receptor-gamma protects ERBB2-positive breast cancer cells from palmitate toxicity. Breast Cancer Res, 11, 16.
  37. Kumar AP, Loo SY, Shin SW, et al (2013). Targeting MnSOD in basal breast carcinoma using agonists of PPAR$\gamma$: a new strategy for enhancing chemosensitivity. Antioxid Redox Signal, [Epub ahead of print]

Cited by

  1. Effects of Rapamycin on Cell Apoptosis in MCF-7 Human Breast Cancer Cells vol.15, pp.24, 2015,