AR, the cell cycle, and prostate cancer

Abstract

The androgen receptor (AR) is a critical effector of prostate cancer development and progression. The dependence of this tumor type on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function (achieved either through ligand depletion and/or the use of AR antagonists) is the first line of therapeutic intervention. These strategies are initially effective, and induce a mixed response of cell cycle arrest or apoptosis in prostate cancer cells. However, recurrent, incurable tumors ultimately arise as a result of inappropriately restored AR function. Based on these observations, it is imperative to define the mechanisms by which AR controls cancer cell proliferation. Mechanistic investigation has revealed that AR acts as a master regulator of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent kinase (CDK) activity, induce phosphorylation/inactivation of the retinoblastoma tumor suppressor (RB), and thereby govern androgen-dependent proliferation. These functions appear to be independent of the recently identified TMPRSS2-ETS fusions. Once engaged, several components of the cell cycle machinery actively modulate AR activity throughout the cell cycle, thus indicating that crosstalk between the AR and cell cycle pathways likely modulate the mitogenic response to androgen. As will be discussed, discrete aberrations in this process can alter the proliferative response to androgen, and potentially subvert hormonal control of tumor progression.

Figure 1. AR-cell cycle crosstalk.

Activated AR stimulates the accumulation of cyclin D1 (D1), through mammalian Target of Rapamycin (mTOR), to activate CDK4 and promote phosphorylation of the retinoblastoma (RB) tumor suppressor. In addition, AR-induced expression of p21^Cip1 and degradation of p27^Kip1 further enhance cycD1/CDK4 and cycE/CDK2-dependent inactivation of RB and allow expression of E2F target genes like cyclin A (CycA). Cyclin A in turn activates CDK2 to drive G1-S phase transition. Subsequently engaged components of the cell cycle machinery then impinge on AR to regulate the androgen response. Elevated cyclin D1 acts as in a negative feedback loop to attenuate AR activity, thereby modulating androgen action. In G2-phase, CDK1 promotes the phosphorylation and activation of AR. However, AR is degraded in M-phase and is purposed to be a “licensing factor” for DNA replication. Components that suppress AR function are outlined in red, whereas positive effectors of AR activity are outlined in green.