Pathogenesis of prostate cancer and hormone refractory prostate cancer

Abstract

Prostate cancer is the second most common malignancy in males and the leading cause of cancer death. Prostate cancer is initially androgen dependent and relies upon the androgen receptor (AR) to mediate the effects of androgens. The AR is also the target for therapy using antiandrogens and LHRH analogues. However, all cancers eventually become androgen independent, often referred to as hormone refractory prostate cancer. The processes involved in this transformation are yet to be fully understood but research in this area has discovered numerous potential mechanisms including AR amplification, over-expression or mutation and alterations in the AR signaling pathway. This review of the recent literature examines the current knowledge and developments in the understanding of the molecular biology of prostate cancer and hormone refractory prostate cancer, summarizing the well characterized pathways involved as well as introducing new concepts that may offer future solutions to this difficult problem.

Keywords: Prostate cancer; refractory androgen receptor.

Figure 1

Intracellular metabolism of androgens. AR - androgen receptor, T - Testosterone, DHEA - Dehydroepiandrosterone, DHT-Dihydrotestosterone, hsp - heat shock protein, ARE - Androgen response elements

Figure 2

Schematic representation of androgen receptor showing the NTD - N-terminal domain, DBD - DNA-binding domain, LBD - ligandbinding domain, AF - activation function domains 1 in N-terminus and 2 in LBD

Figure 3

Schematic representation of adrenal, testicular and prostatic intracrine androgen metabolism. CYP17 - steroid 17-alpha-hydroxylase, CYP11a - steroid 11 - alpha - hydroxylase, DHEA dehydroepiandrosterone, 5a - A-5-androstane-3, 17 dione, DHT - dihydrotestosterone, 5a-diol - 5a androstane-3, 17 diol

Figure 4

Schematic representation of the interactions between androgen receptor, MAPK and Akt signalling. IGFR - insulin-like growth factor receptor, EGFR - epidermal growth factor receptor, FGFR - fibroblast growth factor receptor, MAPK mitogen-activated protein kinases, MAPKK - MAPK kinases, MAPKKK - MAPKK kinases, DLK - Dual leucine zipper bearing kinase, MEK - Mitogen-activated protein kinase/ERK kinase, ERK - extracellular signal-related kinase, JNK - c-Jun-N-terminal kinases, PI3K- phosphoinositol 3-kinase, PIP - phosphatidylinositol phosphate, AR - androgen receptor, P - phosphorylation, ARE - androgen response elements