Cellular and molecular signatures of androgen ablation of prostate cancer

Androgen ablative therapy is the cornerstone of treatment for metastatic prostate cancer and some cases of high-risk, localized disease. This is only palliative, however, since castration-recurrent disease typically occurs. Accordingly, intense research efforts focus upon achieving a better understanding of the cellular and molecular responses to androgen ablation and their roles in facilitating the transition to recurrence. In this chapter, we discuss how diminished androgen receptor (AR) signaling represents the pivotal mediator of a tightly coordinated signaling response that manifests in loss of AR expression, growth arrest, neuroendocrine differentiation (NED), and survival. Classic androgen-deprivation therapy has evolved to include approaches aimed at achieving complete suppression of AR signaling through the utilization of AR antagonists and inhibitors of androgen metabolism. This mediates repression of AR function at multiple levels by abrogating its transcriptional activity, increasing its turnover, and reducing translation of its transcript. Consequently, this leads to cellular trans-differentiation from an epithelial to neuroendocrine phenotype. NED cells figure critically in disease progression by virtue of secreting growth-promoting neurotrophic factors, possessing features of cancer stem cells, and surviving in the absence of androgen. Along these lines, phosphatidylinositol-3 kinase (PI3K)-Akt signaling is hyperactivated in response to androgen ablation and functions as a dominant antiapoptotic pathway, especially in the context of PTEN-mutant cancers such as LNCaP. Interestingly, mammalian target of rapamycin (mTOR) is implicated as a critical sensor of androgen signaling and an integrator of androgen ablation-induced AR down-regulation, PI3K-Akt hyperactivation, and NED. The marked effects of androgen ablation are due in large part to widespread changes in AR-regulated gene expression which produce a diagnostic androgen withdrawal expression signature. Although not well defined, we discuss potential mechanisms and gene product interactions that might explain how these translate into the molecular and biological features of androgen ablation.