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.
Highlights
It is suggested that Prostate Cancer (PCa) progresses from a castration-sensitive PCa (CSPC) to the androgen deprivation therapy (ADT) resistant tumor termed as castration-resistant PCa (CRPC)
Important examples are the recently clinically approved androgen receptor (AR) antagonists Enzalutamide (Enz), Apalutamide (Apa) and Darolutamide that are used in therapy of metastatic CRPC (mCRPC), mCSPC, and nmCRPC, respectively [27,28,29]
Induce cellular senescence in PCa. This important AR pathway is mediated by membrane and cytosolic transduction factors including PI3K, Src family, Akt and mammalian target of rapamycin (mTOR)
Summary
PCa is the most frequently diagnosed and the second leading lethal cancer among men in Western countries where the incidence has a strong correlation with aging [1]. It is suggested that PCa progresses from a castration-sensitive PCa (CSPC) to the androgen deprivation therapy (ADT) resistant tumor termed as castration-resistant PCa (CRPC) Both CSPC and CRPC can metastasize leading to the lethal aggressive cancer [4]. Many co-regulators are recruited, which act as chromatin modifiers, transcription and mediator complexes, the AR mediates transactivation or transrepression of target genes [16,17,18,19] In addition to this genomic activity, a rapid non-genomic signaling of AR is known. AR protein stability; (4) changes in the expression of AR co-regulators to maintain or enhance AR mediated transactivation of target genes; (5) post-translational modifications of AR; and (6) activation of growth factors, kinases, and cytokine signaling pathways that crosstalk with AR signaling [25,26]. Important examples are the recently clinically approved AR antagonists Enzalutamide (Enz), Apalutamide (Apa) and Darolutamide that are used in therapy of mCRPC, mCSPC, and nmCRPC, respectively [27,28,29]
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