Molecular Mechanisms of Castration-Resistant Prostate Cancer Progression

Abstract

Hormone-refractory prostate cancer is the result of regrowth of prostate cancer cells that have adapted to the hormone-deprived environment of the prostate. The process by which castrationresistant prostate cancer (CRPC) cells are generated appears to be varied. The complex mechanism of hormone resistance has been the topic of research in most laboratories that have analyzed the process from different angles. This review compiles research findings that explain the methods of development of hormone resistance in prostate cancer. Research data show many different processes to be involved in the acquisition of hormone resistance. Interestingly, one observes interdependence between these processes, indicating a complex network at play in the development of hormone resistance. Cytokines such as IL-6 have been shown to initiate an alternative signaling pathway, compared with the androgen receptor signaling pathway, in CRPC. IL-6 has been proposed to be the effector of the intracrine signaling pathway by influencing the levels of metabolic enzymes. Neuroendocrine cells are present at low levels in normal prostate, and signify the transitory phase of normal hormone-sensitive cells to hormone-refractory cells. IL-6 induces growth of neuroendocrine cells or neuroendocrine-like features in cells in CRPC. The increased presence of neuroendocrine cells in CRPC signifies a change in the prostate cell microenvironment. The stromal microenvironment also influences the development of CRPC in the hormone-refractory stage. In addition, intracrine androgen metabolic enzymes play a significant role in the development of the hormone refractory process. Despite hormone ablation, there is a residual level of hormones in cells due to active intracrine metabolic pathways. It is acknowledged that the androgen receptor plays the most influential role in development of prostate cancer. In addition to mutation and amplification, the androgen receptor has been characterized and shown to differ in sequence in CRPC compared with the androgen-sensitive prostate cancer cells. These variants of the androgen receptor through sequence changes may preserve the basic function of the molecule, but have far-reaching consequences on the cell as a †

Androgen Signaling in Prostate Cancer

“…A number of cell surface receptors including epidermal growth factor receptor (EGFR), interleukin (IL)-6 and IL-8 receptors, insulin-like growth factor 1 (IGF-1) receptor, and Her2/neu have been implicated in cross talk with AR to drive ligandindependent signaling or to sensitize AR to subphysiologic androgen concentrations (Mellinghoff et al 2004;Guo et al 2006;Ponguta et al 2008;Dutt and Gao 2009). Intracellular kinases such as mitogen-activated protein kinase (MAPK), as well as its effectors Src and ERK1/2, and PI3K/Akt have also been shown to drive prostate cancer progression (Guo et al 2006).…”

Selective Roles for cAMP Response Element-binding Protein Binding Protein and p300 Protein as Coregulators for Androgen-regulated Gene Expression in Advanced Prostate Cancer Cells

“…AR amplification or gain of func-* This work was supported, in whole or in part, by National Institutes of Health tion mutations can allow AR activation by castration levels of androgens or even by non-androgenic steroids and antiandrogens, which do not activate the wild-type AR. Enhanced activity of other signaling pathways or altered androgen metabolism can also enhance AR activity (4). Increased levels or activity of coregulators or posttranslational modifications to AR or coregulators as a result of deregulation of other signaling pathways can also contribute to the ADI phenotype (5,6).…”

A multicentre analysis of abiraterone acetate in Canadian patients with metastatic castration resistant prostate cancer

“…2 This can be a consequence of a hypersensitive phenotype of the androgen receptor, which is often compounded by an increase in extragonadal or de novo intratumoralandrogen production. 3 Targeting pathways that deplete the source of additional androgens can alter the biology and clinical course of CRPC. 2 Abiraterone acetate (abiraterone) is a novel oral agent that specifically inhibits the activity of CYP17 (17-[alpha]hydroxylase/17, 20-lyase), a key enzyme required for biosynthesis of androgens in the adrenal glands and in tumour tissues.…”