Genistein Represses Telomerase Activity via Both Transcriptional and Posttranslational Mechanisms in Human Prostate Cancer Cells

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 genisteininduced 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)

Anti‑inflammatory drug resistance selects putative cancer stem cells in a cellular model for genetically predisposed colon cancer

“…At the mechanistic level, β-catenin transcriptionally regulates the gene encoding Tert, which represents the enzymatic subunit of the telomerase enzyme (36). Furthermore, several natural compounds and their derivatives, as well as synthetic small molecules, achieve a potent inhibition of telomerase in cell culture models for epithelial cancers (37)(38)(39)(40). In this regard, the present colonic epithelial cell culture model differing in the expression of the tumor suppressor Apc gene, together with a model for Apc -/-drug-resistant telomerase-expressing colonic cancer stem cells, may provide novel mechanism-based experimental approaches for the identification of efficacious stem cell-targeted therapeutic agents.…”

Effects of genistein on β‐catenin signaling and subcellular distribution of actin‐binding proteins in human umbilical CD105‐positive stromal cells

“…Genistein has been shown to suppress the proliferation of many types of cancer cell (Akiyama et al, 1987;Zwiller et al, 1991;Li and Sarkar, 2002;Jagadeesh et al, 2006;El Touny and Banerjee, 2007;Li et al, 2009). Although genistein was considered as a specific TPK inhibitor (Akiyama et al, 1987;Akiyama and Ogawara, 1991), additional evidence has been provided that genistein exerts multiple effects on cell growth including inhibition of neovascularization or angiogenesis (Fotsis et al, 1993), topoisomerase II (Okura et al, 1988), oncogene product activity (Zwiller et al, 1991), telomerase activity (Jagadeesh et al, 2006), Akt inhibition (Li and Sarkar, 2002;El Touny and Banerjee, 2007), and modulation of epigenetic events such as DNA methylation and/or histone acetylation (Li et al, 2009).…”

“…Although genistein was considered as a specific TPK inhibitor (Akiyama et al, 1987;Akiyama and Ogawara, 1991), additional evidence has been provided that genistein exerts multiple effects on cell growth including inhibition of neovascularization or angiogenesis (Fotsis et al, 1993), topoisomerase II (Okura et al, 1988), oncogene product activity (Zwiller et al, 1991), telomerase activity (Jagadeesh et al, 2006), Akt inhibition (Li and Sarkar, 2002;El Touny and Banerjee, 2007), and modulation of epigenetic events such as DNA methylation and/or histone acetylation (Li et al, 2009). In this study, we demonstrated that genistein significantly induced a dose-dependent reduction of intracellular Ca 2þ in human umbilical CD105-positive MSCs (Fig.…”

Telomerase Inhibitors and Activators: Pharmaceutical Importance

“…Genistein inhibits the transcription of hTERT in breast MCF10AT benign cells and MCF7 cancer cells [62]. Genistein also decreases telomerase activity in prostate cancer cells [63,64]. Ouchi et al showed that the expression of hTERT and c-myc mRNA was downregulated by genistein in prostate cancer cells [63].…”