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  • Title: Mechanisms of prostate cancer cell survival after inhibition of AR expression.
    Author: Cohen MB, Rokhlin OW.
    Journal: J Cell Biochem; 2009 Feb 15; 106(3):363-71. PubMed ID: 19115258.
    Abstract:
    Recent reports have shown that the AR is the key determinant of the molecular changes required for driving prostate cancer cells from an androgen-dependent to an androgen-independent or androgen depletion-independent (ADI) state. Several recent publications suggest that down-regulation of AR expression should therefore be considered the principal strategy for the treatment of ADI prostate cancer. However, no valid data is available about how androgen-dependent prostate cancer cells respond to apoptosis-inducing drugs after knocking down AR expression and whether prostate cancer cells escape apoptosis after inhibition of AR expression. This review will focus on mechanisms of prostate cancer cell survival after inhibition of AR activity mediated either by androgen depletion or by targeting the expression of AR by siRNA. We have shown that knocking down AR expression by siRNA induced PI3K-independent activation of Akt, which was mediated by calcium/calmodulin-dependent kinase II (CaMKII). We also showed that the expression of CaMKII genes is under AR control: active AR in the presence of androgens inhibits CaMKII gene expression whereas inhibition of AR activity results in an elevated level of kinase activity and in enhanced expression of CaMKII genes. This in turn activates the anti-apoptotic PI3K/Akt pathways. CaMKII also express anti-apoptotic activity that is independent from the Akt pathway. This may therefore be an important mechanism by which prostate cancer cells escape apoptosis after androgen depletion or knocking down AR expression. In addition, we have found that there is another way to escape cell death after AR inhibition: DNA damaging agents cannot fully activate p53 in the absence of AR and as a result p53 down stream targets, for example, microRNA-34, cannot be activated and induce apoptosis. This implies that there may be a need for re-evaluation of the therapeutic approaches to human prostate cancer.
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