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

D. J. Mulholland, S. Dedhar, H. Wu, C. C. Nelson

Research output: Contribution to journalArticlepeer-review

185 Scopus citations


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 β (GSK3β) 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 AktSer473 and integrin-linked kinase expression, both of which promote Ser9 phospho-inhibition of GSK3β and inactivation of apoptotic factors. Sufficient evidence also suggests that GSK3β is not only a critical regulator of proproliferative signalling but also a promiscuous one as PI3K/Akt pools of GSK3β are, at least in part, functionally interchangeable with those of the Wnt/β-catenin pathway. Thus, GSK3β may serve not only as a mediator of PI3K/Akt activation but may also regulate the potent transactivation and proproliferative effects that Wnt3a and β-catenin confer upon AR. These data suggest that prostate-specific activation of GSK3β may serve as a viable pharmacological option. Thus, in this review, we emphasize that temporal changes in GSK3β 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.

Original languageEnglish
Pages (from-to)329-337
Number of pages9
Issue number3
StatePublished - 19 Jan 2006
Externally publishedYes


  • Androgen-independent prostate cancer
  • GSK3β
  • PTEN


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