PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer

Abstract

Prostate cancer (PrCa) is characterized by progression from an androgen-dependent phenotype to one that is inevitably androgen independent (AI) and lethal. Recent evidence strongly suggests that the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and androgen receptor (AR) signalling pathways provide prostatic epithelium with the necessary signalling events to escape the apoptotic response associated with androgen withdrawal therapy. Silencing of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and glycogen synthase kinase b (GSK3b) are frequently associated with advanced PrCa systems and likely serve critical roles in promoting AR and PI3K/Akt gain-of-function. That PTEN negatively regulates AR and is sufficient to promote metastatic PrCa in murine models strongly implies its role as a gatekeeper of progressive PrCa. In human PrCa, PTEN loss is correlated with substantial increases in Akt Ser473 and integrin-linked kinase expression, both of which promote Ser 9 phospho-inhibition of GSK3b and inactivation of apoptotic factors. Sufficient evidence also suggests that GSK3b is not only a critical regulator of proproliferative signalling but also a promiscuous one as PI3K/Akt pools of GSK3b are, at least in part, functionally interchangeable with those of the Wnt/b-catenin pathway. Thus, GSK3b may serve not only as a mediator of PI3K/Akt activation but may also regulate the potent transactivation and proproliferative effects that Wnt3a and b-catenin confer upon AR. These data suggest that prostate-specific activation of GSK3b may serve as a viable pharmacological option. Thus, in this review, we emphasize that temporal changes in GSK3b and PTEN expression during progression to AI PrCa are important factors when considering the potential for therapies targeting the oncogenic contributions of PI3K/Akt and AR signalling pathways.

Synergistic induction of apoptosis in human leukemia T cells by the Akt inhibitor perifosine and etoposide through activation of intrinsic and Fas-mediated extrinsic cell death pathways

“…GSK-3h is rapidly emerging as a critical regulator of cell cycle (29), whereas FoxO1 is involved in the control of Fas ligand gene expression (30). Furthermore, the activation state of the survival protein Erk1/2 and the proapoptotic SAPK/JNK pathway was followed, which previously have been reported to be affected by perifosine treatment (20).…”

Oncogenic signaling of class I PI3K isoforms

“…As a measure of Akt activity linked to signaling from the class I p110 isoforms, we analysed the phosphorylation levels of direct Akt substrates GSK3b and FoxO1 in transfected CEF. GSK3b is a proapoptotic kinase (Mulholland et al, 2006) and also negatively regulates the cell cycle (Dong et al, 2005). GSK3b is phosphorylated by Akt at serine 9 and consequently inactivated (Shaw et al, 1997).…”

Inhibition of Akt pathways in the treatment of prostate cancer

“…5 Other recently discovered phosphatases include C-terminal modulator protein and PH domain leucine-rich repeat protein phosphatase, both of which may be significant in Akt regulation. 8 Direct deactivation of Akt is also possible. Protein phophatases (PP1 and PP2a) both govern the regulatory activity of many intracellular messengers including Akt through dephosphophorylation.…”

“…20 However, the most consistent finding in this disease is the silencing of PTEN and subsequent increase in Akt signaling. 8 PTEN may be lost by deletion, mutation or epigenetic mechanisms. 5 Up to half of the patients CaP tissue specimens show inactivation of PTEN with increasing incidence of this finding in metastatic deposits and AI disease, emphasizing its possible importance in tumor progression.…”