Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles

Abstract

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms.

Keywords: Jak2; Stat5a/b; androgen receptor; antiandrogen; castrate-resistant; metastasis; prostate cancer.

Figure 1. Molecular mechanisms driving CRPC

Development of CRPC has been attributed to numerous potential molecular mechanisms, including: 1) somatic mutations of AR resulting in increased affinity for ligands; 2) amplification of the AR gene locus; 3) intracrine biosynthesis of androgens in prostate cancer cells from adrenal steroids and cholesterol; 4) expression of constitutively active, ligand-independent AR splice variants; 5) non-canonical activation of AR by protein kinase signaling pathways in the absence of ligand by receptor tyrosine kinases (RTK); 6) AR-independent mechanisms operating outside of the AR signaling axis which promote castrate-resistant growth of prostate cancer.

Figure 2. Canonical Jak2-Stat5a/b signaling in prostate cancer cells and functional interaction with AR signaling

Various levels of inhibition are possible in the Stat5a/b signaling cascade to block Stat5a/b target gene expression, including targeting of cytokine receptor activation, Jak2 kinase-mediated phosphorylation, and Stat5a/b dimerization, DNA binding and transcriptional activity. Physical interaction between Stat5a/b and AR has been reported, providing a mechanistic basis for crosstalk between these two pathways, which results in reciprocal synergistic effects on nuclear localization and transcriptional activity. Depicted are known Stat5a/b target genes Bcl-xL and cyclin D1 and AR target gene PSA. Abbreviations: AR, androgen receptor; ARE, androgen response element; CYT, cytokine; CYTR, cytokine receptor; DHT, dihydrotestosterone; GAS, gamma-interferon activation sequence; GF, growth factor; HSP, heat shock protein; pY, phosphotyrosine.

Figure 3. Therapeutic targeting of Stat5a/b inhibits growth of prostate cancer through AR-dependent and AR-independent mechanisms

Disruption of Stat5a/b signaling inhibits growth and viability of prostate cancer through two distinct mechanisms, serving as a potential dual strategy to eliminate prostate cancer cells. First, targeting of Stat5a/b inhibits the abilities of Stat5a/b to protect antiandrogen-liganded AR from proteasomal degradation and enhance AR signaling, including downstream molecular events such as AR nuclear localization, chromatin binding, and activation of target gene expression in prostate cancer cells. Second, targeting of Stat5a/b prevents the induction of AR-independent, Stat5a/b-regulated genes involved in proliferation and survival of prostate cancer cells.