The AR dependent cell cycle: mechanisms and cancer relevance

Abstract

Prostate cancer cells are exquisitely dependent on androgen receptor (AR) activity for proliferation and survival. As these functions are critical targets of therapeutic intervention for human disease, it is imperative to delineate the mechanisms by which AR engages the cell cycle engine. More than a decade of research has revealed that elegant intercommunication between AR and the cell cycle machinery governs receptor-dependent cellular proliferation, and that perturbations in this process occur frequently in human disease. Here, AR-cell cycle interplay and associated cancer relevance will be reviewed.

Fig. 1

Regulation of cell cycle by the androgen receptor. Liganded AR induces the translation and accumulation of D-type cyclins by engaging the mammalian Target of Rapamycin (mTOR) complex, which mediates cdk4/6 activation and subsequent phosphorylation and inactivation of the retinoblastoma tumor suppressor (RB). Concomitantly, AR further impinges on G1-S progression by inducing expression of p21^cip1 and degradation of p27^kip1, promoting enhanced cdk4/6 and cdk2 dependent inactivation of RB and progression through G1. Pathways requisite for entry into S phase are initiated upon RB inactivation, which induce the activity of the E2F family of transcription factors responsible for the production cyclin A, activation of cdk2 (via cyclin A binding), and entry into S-phase. Additionally, E2F1 directly induces the expression of AR itself, potentially enhancing progression through the cell cycle.

Fig. 2

Contribution of cell cycle machinery to androgen receptor activity. The androgen receptor (AR) is regulated by many factors whose functions are also responsible for modulating cell cycle control. Cyclin-dependent kinases (CDKs), cyclins, members of the Cdc25 family of phosphatases, and the RB/E2F axis all contribute to this regulation. AR is degraded as cell progress through mitosis. Arrows terminating in “+” indicate activities resulting in upregulation of AR activity, while negative regulation is indicated by “−”.