Down-regulation of hTERT expression plays an important role in 15-deoxy-Delta(12,14)-prostaglandin J(2)-induced apoptosis in cancer cells

作者：Moriai Mikako; Tsuji Naoki; Kobayashi Daisuke; Kuribayashi Kageaki; Watanabe Naoki^*

来源：International Journal of Oncology, 2009, 34(5): 1363-1372.

DOI：10.3892/ijo_00000263

• 15-deoxy-Delta(12,14)-prostaglandin
• human telomerase reverse transcriptase
• estrogen receptor
• prostaglandin
• small inhibitory RNA

The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been shown to possess antineoplastic activity in human cancers of various origins. However, the mechanism of the antineoplastic activity of 15d-PGJ(2) remains to be completely elucidated. It has been reported that inhibiting the expression of human telomerase reverse transcriptase (hTERT), a major determinant of telomerase activity, induces rapid apoptosis in cancer cells. In this study, we investigated the effect of 15d-PGJ(2) on hTERT expression. Treatment with 30 mu M 15d-PGJ(2) for 72 It induced apoptosis in the colon cancer cells LS 180. 15d-PGJ(2) treatment decreased hTERT protein expression in a dose-dependent manner. Down-regulation of hTERT expression by hTERT-specific small inhibitory RNA induced apoptosis. These results indicate that the down-regulation of hTERT expression by 15d-PGJ(2) plays an important role in its proapoptotic properties. Since 15d-PGJ(2) reduced hTERT mRNA expression, we examined the effect of 15d-PGJ(2) on the DNA-binding activity of c-Myc, specificity protein 1 (Sp1) and estrogen receptor (ER) to the hTERT gene promoter using an electrophoretic mobility shift assay. 15d-PGJ(2) attenuated the DNA-binding of all three transcriptional factors. Further, we observed that 15d-PGJ(2) inhibited the DNA binding of these factors by different mechanisms; suppressed c-Myc mRNA expression, enhanced Sp1 protein degradation via the ubiquitin-proteasome pathway and inhibited ER beta phosphorylation at serine residues. We conclude that hTERT down-regulation by 15d-PGJ(2) plays an important role in its proapoptotic properties. Furthermore, 15d-PGJ(2) inhibits the transcriptional activity of c-Myc, Sp1 and ER by three different mechanisms and results in the transcriptional repression of the hTERT gene.

• 出版日期2009-5