Inhibition of estrogen receptor beta-mediated human telomerase reverse transcriptase gene transcription via the suppression of mitogen-activated protein kinase signaling plays an important role in 15-deoxy-Delta(12,14)-prostaglandin J(2)-induced apoptosis in cancer cells.
The nuclear hormone 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 ERbeta, 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 ERbeta 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 ERbeta-mediated hTERT gene transcription by suppressing ERbeta phosphorylation via the inhibition of MAP kinase signaling.
Kondoh
Kei
K
Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Japan.
Tsuji
Naoki
N
Asanuma
Koichi
K
Kobayashi
Daisuke
D
Watanabe
Naoki
N
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D004273:DNA, Neoplasm; D047629:Estrogen Receptor beta; D034741:RNA, Small Interfering; D010768:Phosphoserine; C509186:TERT protein, human; D019098:Telomerase; D010749:Phosphoprotein Phosphatases; D015230:Prostaglandin D2