PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells

Abstract

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 0 -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 insulinlike growth factor-I receptor (IGF-IR) protein levels and a 49-64% reduction in cell surface IGF-IR expression.[ 35 S]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.

Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer

“…18,20 Following an overnight serum starve, we observed phosphorylation of Akt in unstimulated PC3 and LNCaP cells, of ERKs in DU145, and of p38 in all three cell lines (Fig 4a). The detectable basal level of phospho-Akt in PC3 and LNCaP cells has been previously reported 31 and is a predictable consequence of inactivating PTEN mutation. Detection of other phosphorylated intermediates suggested persisting IGF1R activation in serum-starved cells, perhaps due to autocrine IGF-II production.…”

“…Indeed that study indicated that in PC3 cells, IGF signalling provides a more pronounced survival effect in the absence of PTEN. 31 Suppression of PTEN expression in PC12 cells with PTEN antisense has also been shown to enhance the protective effect of IGF-1 against etoposideinduced apoptosis. 32 As discussed previously 22 and indicated in Figure 1c, profound IGF1R downregulation does not persist for the duration of the clonogenic survival assay, but levels at the time of cell seeding are likely to be important in determining survival.…”

PTEN and Akt expression during growth of human ovarian follicles

“…Overexpression of PTEN in vivo and vitro in different cell lines induces the arrest of the cell cycle and/or apoptosis [22][23][24]. Taken together, expression of PTEN in granulosa cells in rather small follicles, which decrease the potential for proliferation as an inappropriate differentiation signal, might lead to apoptosis of granulosa cells followed by follicle atresia, although further studies are needed to investigate whether PTEN is implicated in the apoptosis of granulosa cells.…”

Role of insulin-like growth factor 1 receptor signalling in cancer

“…Another aspect on a unique role of IGF-1R in cancer is based on several recent findings that loss of suppressor oncogenes as well as activation of proto-oncogenes is related to IGF-1R function and activity (Baserga, 1994;Girnita et al, 2000;Werner and Le Roith, 2000;Girnita et al, 2003;Zhao et al, 2004). This area of research deserves a separate attention and is discussed in the next section of this review.…”