Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Abstract

The androgen receptor (AR) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different AR antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key cellular response for the treatment of PCa. Surprisingly, while physiological levels of androgens promote growth, supraphysiological androgen levels (SAL) inhibit PCa growth in an AR-dependent manner by inducing cell senescence in cancer cells. Thus, oppositional acting ligands, AR antagonists, and agonists are able to induce cellular senescence in PCa cells, as shown in cell culture model as well as ex vivo in patient tumor samples. This suggests a dual AR-signaling dependent on androgen levels that leads to the paradox of the rational to keep the AR constantly inactivated in order to treat PCa. These observations however opened the option to treat PCa patients with AR antagonists and/or with androgens at supraphysiological levels. The latter is currently used in clinical trials in so-called bipolar androgen therapy (BAT). Notably, cellular senescence is induced by AR antagonists or agonist in both androgen-dependent and castration-resistant PCa (CRPC). Pathway analysis suggests a crosstalk between AR and the non-receptor tyrosine kinase Src-Akt/PKB and the PI3K-mTOR-autophagy signaling in mediating AR-induced cellular senescence in PCa. In this review, we summarize the current knowledge of therapeutic induction and intracellular pathways of AR-mediated cellular senescence.

Keywords: PKB/Akt; Src; androgen receptor antagonist; antiandrogen; bipolar androgen therapy; cellular senescence; prostate cancer; supraphysiological androgen levels.

Figure 1

Androgen at supraphysiological level (SAL) induces cellular senescence through the PI3K/Src/Akt/mTOR pathway. In the cytoplasm, androgen receptor (AR) forms a complex with heat shock proteins (HSPs). Activation of the AR is triggered by binding of androgens (AR agonist) to the receptor. Androgen-activated AR dissociates from HSPs, and subsequently mediates AR signaling. (1) The majority of activated AR forms homodimer and translocates into the nucleus, where it binds to androgen response element (ARE) at the promoter of the target genes and mediates transcription. (2) A minor fraction of activated AR remains in the cytoplasm, interacts with and functions through several signaling molecules, e.g., Src, PI3K/Akt, S6, Ras/Raf1, MAPK/ERK. Interestingly, co-treatment of SAL with inhibitors of PI3K (3-MA), Src family members (PP2), Akt (Akti), or mTOR (Rapamycin) inhibits senescence induction. This indicates that Src/PI3K/Akt/mTOR pathway is involved in SAL-mediated cellular senescence in PCa cells.

Figure 2

AR antagonist induces cellular senescence in PCa through the Src/Akt pathway. Binding of AR antagonist to AR leads to conformational change of AR. AR antagonists compete with androgens for binding to AR. (1) Moreover, some AR antagonists reduce AR nuclear translocation, chromatin association and DNA binding. (2) As a result, the majority of AR resides in the cytoplasm and may interact with cytoplasmic factors to mediate cellular senescence. Co-treatment of the AR antagonist atraric acid with the inhibitors of Src (PP2) or Akt (Akti) reduce cell senescence suggesting that Src/Akt pathway is involved in AR antagonist-induced cellular senescence in PCa cells.