Genistein Represses Telomerase Activity via Both Transcriptional and Posttranslational Mechanisms in Human Prostate Cancer Cells
Open Access
- 15 February 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 66 (4), 2107-2115
- https://doi.org/10.1158/0008-5472.can-05-2494
Abstract
Genistein, the most abundant isoflavone present in soybean has antiproliferative effects on a variety of cancer cells, including prostate cancer. However, the molecular mechanism of antiproliferative effects of genistein is not entirely understood. Because the activation of telomerase is crucial for cells to gain immortality and proliferation ability, we examined the role of genistein in the regulation of telomerase activity in prostate cancer cells. Here, we show that genistein-induced inhibition in cell proliferation is associated with a reduction in telomerase activity. Using reverse transcriptase-PCR and hTERT promoter activity assays, we showed that genistein decreased hTERT expression and transcriptional activity dose-dependently. Using various deleted hTERT promoter constructs, we defined that the hTERT core promoter is enough to observe the genistein-induced repression of hTERT transcriptional activity. Because c-Myc is involved in transcriptional regulation of hTERT, c-Myc expression was examined. A dose-dependent decrease in c-Myc message and proteins was observed with genistein treatment. These results indicate that genistein represses hTERT transcriptional activity via the down-regulation of c-Myc expression. However, genistein-induced repression of hTERT transcriptional activity was not blocked by the mutation of c-Myc at the hTERT promoter, suggesting that additional factors are involved in genistein-dependent repression of telomerase activity. Interestingly, we observed that genistein down-regulates the activation of Akt thereby phosphorylation of hTERT and inhibits its translocation to the nucleus. These results show for the first time that genistein represses telomerase activity in prostate cancer cells not only by repressing hTERT transcriptional activity via c-Myc but also by posttranslational modification of hTERT via Akt. (Cancer Res 2006; 66(4): 2107-15)Keywords
This publication has 45 references indexed in Scilit:
- Genistein induces cell growth inhibition in prostate cancer through the suppression of telomerase activityInternational Journal of Urology, 2005
- Protein kinase C modulates telomerase activity in human cervical cancer cellsExperimental & Molecular Medicine, 2001
- NF-κB Regulates Transcription of the Mouse Telomerase Catalytic SubunitPublished by Elsevier BV ,2000
- Effects of Genistein, A Soybean-Derived Isoflavone, on Proliferation and Differentiation of B16-BL6 Mouse Melanoma CellsJournal of Asian Natural Products Research, 1999
- Myc activates telomeraseGenes & Development, 1998
- Influence of portein tyrosine phosphorylation on the experssion of the c-myc oncogene in cancer of the large bowelJournal of Cellular Biochemistry, 1995
- Specific Association of Human Telomerase Activity with Immortal Cells and CancerScience, 1994
- Effect of the tyrosine kinase inhibitor, genistein, on interleukin-1 stimulated PGE2 production in mesangial cellsBiochemical and Biophysical Research Communications, 1990
- Effect of genistein on topoisomerase activity and on the growth of [VAL 12]Ha-ras-transformed NIH 3T3 cellsBiochemical and Biophysical Research Communications, 1988
- Identification of a specific telomere terminal transferase activity in tetrahymena extractsCell, 1985