Zhao Hong, Dupont Joelle, Yakar Shoshana, Karas Michael, LeRoith Derek
Diabetes Branch, NIDDK, National Institute of Health, Room 8D12, Bldg 10, Bethesda, MD 20892-1758, USA.
Oncogene. 2004 Jan 22;23(3):786-94. doi: 10.1038/sj.onc.1207162.
PTEN is a tumor suppressor gene that is frequently mutated in human tumors. It functions primarily as a lipid phosphatase and plays a key role in the regulation of phosphatidylinositol-3'-kinase. PTEN appears to play a crucial role in modulating apoptosis by reducing the levels of PtdIns(3,4,5)P3, a phospholipid that activates AKT, a central regulator of apoptosis. To understand the role of PTEN in regulating cell proliferation and apoptosis, we stably overexpressed PTEN in PC3 cells, which are prostate cancer cells that lack PTEN. Overexpression of PTEN in two different clones inhibited cell proliferation and increased serum starvation-induced apoptosis, as compared to control cells. Interestingly, PTEN overexpression resulted in a 44-60% reduction in total insulin-like growth factor-I receptor (IGF-IR) protein levels and a 49-64% reduction in cell surface IGF-IR expression. [35S]methionine pulse experiments in PC3 cells overexpressing PTEN demonstrated that these cells synthesize significantly lower levels of the IGF-IR precursor, whereas PTEN overexpression had no effect on IGF-IR degradation. Taken together, our results show that PTEN can regulate cell proliferation and apoptosis through inhibition of IGF-IR synthesis. These results have important implications for understanding the roles of PTEN and the IGF-IR in prostate cancer cell tumorigenesis.
PTEN是一种肿瘤抑制基因，在人类肿瘤中经常发生突变。它主要作为一种脂质磷酸酶发挥作用，在磷脂酰肌醇-3'-激酶的调节中起关键作用。PTEN似乎通过降低磷脂酰肌醇-3,4,5-三磷酸（PtdIns(3,4,5)P3）的水平来调节细胞凋亡，PtdIns(3,4,5)P3是一种激活凋亡核心调节因子AKT的磷脂。为了了解PTEN在调节细胞增殖和凋亡中的作用，我们在PC3细胞中稳定过表达PTEN，PC3细胞是缺乏PTEN的前列腺癌细胞。与对照细胞相比，在两个不同克隆中过表达PTEN抑制了细胞增殖并增加了血清饥饿诱导的细胞凋亡。有趣的是，PTEN过表达导致总胰岛素样生长因子-I受体（IGF-IR）蛋白水平降低44%-60%，细胞表面IGF-IR表达降低49%-64%。在过表达PTEN的PC3细胞中进行的[35S]甲硫氨酸脉冲实验表明，这些细胞合成的IGF-IR前体水平显著降低，而过表达PTEN对IGF-IR降解没有影响。综上所述，我们的结果表明PTEN可以通过抑制IGF-IR合成来调节细胞增殖和凋亡。这些结果对于理解PTEN和IGF-IR在前列腺癌细胞肿瘤发生中的作用具有重要意义。
