Modulating Apoptosis

The mechanisms that determine AD to AI progression can be broadly divided into those that signal through AR and those that do not. Survival signals utilized by cancer cells include the activation of pathways that inhibit apoptosis. Androgen-ablative therapy initially results in growth arrest, followed by proliferation, all while successfully evading apoptosis. Pathways that regulate apoptosis contribute to tumorigenesis and resistance to therapy. Bcl-2 is a potent modulator of the antiapoptotic pathway, which does not function through the AR pathway in prostate cancer cells.

Bcl-2 is normally expressed in the basal cells of the prostate, which are resistant to the effects of androgen withdrawal. Basal cells are also thought to house the putative stem cells of the prostate (see below, Stem Cells). Bcl-2-negative secretory/luminal cells undergo apoptosis in response to androgen deprivation.

High levels of bcl-2 protein expression (as measured by immunohistochemistry) are seen with greater frequency as prostate cancers progress from localized (7%) to AI tumors (67%).86,87 Thus, it appears that bcl-2 enables prostate cancer cells to remain viable despite low levels of androgen and that androgen ablation may select for bcl-2-positive cells that fail to undergo apoptosis. Apoptosis can also be modulated via the AKT pathway. AKT can pho-sphorylate Bad, a proapoptotic peptide. Phos-phorylated Bad binds the cytosolic 14-3-3 protein, whereas dephosphorylated Bad binds and sequesters bcl-2 family proteins, such as bcl-X^ to promote apoptosis.88 Thus, phosphorylation of Bad through AKT will enhance the activity of the anti-apoptotic kinase bcl-2.

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