DAMD 17 - 03 - 1 - 0080 TITLE : Prevention of Prostate Cancer by Inositol Hexaphospate

Inositol hexaphosphate (IP6), the most abundant phosphorylated inositol present in most cereals, nuts, legumes and soybeans has anti-proliferative effects on a variety of cancer cells, including prostate cancer. However, the molecular mechanism of anti-proliferative effects of IP6 is not entirely understood. Since the activation of telomerase is crucial for cells to gain immortality and proliferation ability, we examined the role of IP6 in the regulation of telomerase activity in prostate cancer cells. Here we show that IP6 downregulates TERT message and protein and thereby represses telomerase activity in mouse and human prostate cancer cells dose-dependently. To investigate the molecular mechanism of IP6-induced repression of telomerase activity in prostate cancer cells, we examined one of the key kinases, Akt, that activates TERT by phosphorylation at the serine residue. Activation of TERT is essential for the translocation of TERT to the nucleus and for full telomerase activity. Our data show that IP6 prevents the phosphorylation of Akt and thereby phosphorylation of TERT. As a result, IP6 prevents the translocation of TERT to the nucleus in both mouse and human prostate cancer cells. These results show for the first time that IP6 represses telomerase activity in prostate cancer cells by posttranslational modification of TERT via the Akt and strengthen its role as an anti-cancer agent.