Inhibition of estrogen receptor β-mediated human telomerase reverse transcriptase gene transcription via the suppression of mitogen-activated protein kinase signaling plays an important role in 15-deoxy-Δ12,14-prostaglandin J2-induced apoptosis in cancer cells

The nuclearhormone receptor peroxisome proliferator-activated receptor (PPAR)-gamma plays a role in cancer development in addition to its role in glucose metabolism. The natural ligand of PPAR-gamma, namely, 15-deoxy-Delta(12,14) -prostaglandin J(2) (15d-PGJ(2)), has been shown to possess antineoplastic activity in cancer cells. However, the mechanism underlying its antineoplastic activity remains to be elucidated. Inhibition of the expression of human telomerase reverse transcriptase (hTERT), a major determinant of telomerase activity, reportedly induces rapid apoptosis in cancer cells. In this study, we investigated the effect of 15d-PGJ(2) on hTERT expression. We found that 15d-PGJ(2) induced apoptosis in the MIAPaCa-2 pancreatic cancer cells and dose-dependently decreased hTERT mRNA and protein expression. Down-regulation of hTERT expression by hTERT-specific small inhibitory RNA also induced apoptosis. Furthermore, 15d-PGJ(2) attenuated the DNA binding of estrogen receptor (ER). MIAPaCa-2 expressed only ER beta, and although its expression did not decrease due to 15d-PGJ(2), its phosphorylation was suppressed. Additionally, a mitogen-activated protein kinase (MAPK) kinase inhibitor decreased ER phosphorylation, and 15d-PGJ(2) attenuated MAPK activity. We conclude that hTERT down-regulation by 15d-PGJ(2) plays an important role in the proapoptotic property of the latter. Furthermore, 15d-PGJ(2) inhibits ER beta-mediated hTERT gene transcription by suppressing ER beta phosphorylation via the inhibition of MAP kinase signaling. (c) 2007 Elsevier Inc. All rights reserved.