Jagadeesh Shankar, Banerjee Partha P
Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20057, USA.
Biochem Biophys Res Commun. 2006 Nov 3;349(4):1361-7. doi: 10.1016/j.bbrc.2006.09.002. Epub 2006 Sep 12.
Inositol hexaphosphate (IP6) 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 represses telomerase activity in mouse and human prostate cancer cells dose-dependently. In addition, IP6 prevents the translocation of TERT to the nucleus. Since phosphorylation of TERT by Akt and/or PKCalpha is necessary for nuclear translocation, we examined phosphorylation of Akt and PKCalpha after IP6 treatments. Our results show that IP6 inhibits phosphorylation of Akt and PKCalpha. These results show for the first time that IP6 represses telomerase activity in prostate cancer cells by posttranslational modification of TERT via the deactivation of Akt and PKCalpha.
肌醇六磷酸（IP6）对包括前列腺癌在内的多种癌细胞具有抗增殖作用。然而，IP6抗增殖作用的分子机制尚未完全明确。由于端粒酶的激活对于细胞获得永生和增殖能力至关重要，我们研究了IP6在前列腺癌细胞中端粒酶活性调控中的作用。在此，我们表明IP6在小鼠和人类前列腺癌细胞中剂量依赖性地抑制端粒酶活性。此外，IP6可阻止端粒酶逆转录酶（TERT）向细胞核的转位。由于Akt和/或蛋白激酶Cα（PKCα）对TERT的磷酸化是细胞核转位所必需的，我们检测了IP6处理后Akt和PKCα的磷酸化情况。我们的结果表明，IP6抑制Akt和PKCα的磷酸化。这些结果首次表明，IP6通过使Akt和PKCα失活，对TERT进行翻译后修饰，从而抑制前列腺癌细胞中的端粒酶活性。
