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Review
. 2018 May;15(5):6063-6076.
doi: 10.3892/ol.2018.8123. Epub 2018 Feb 27.

Molecular and cellular mechanisms of castration resistant prostate cancer

Yiqiao Huang  1 , Xianhan Jiang  1 , Xue Liang  1 , Ganggang Jiang  1
Affiliations
Review

Molecular and cellular mechanisms of castration resistant prostate cancer

Yiqiao Huang et al. Oncol Lett. 2018 May.

Abstract

With increases in the mortality rate and number of patients with prostate cancer (PCa), PCa, particularly the advanced and metastatic disease, has been the focus of a number of studies globally. Over the past seven decades, androgen deprivation therapy has been the primary therapeutic option for patients with advanced PCa; however, the majority of patients developed a poor prognosis stage of castration resistant prostate cancer (CRPC), which eventually led to mortality. Due to CRPC being incurable, laboratory investigations and clinical studies focusing on CRPC have been conducted worldwide. Clarification of the molecular pathways that may lead to CRPC is important for discovering novel therapeutic strategies to delay or reverse the progression of disease. A sustained androgen receptor (AR) signal is still regarded as the main cause of CRPC. Increasing number of studies have proposed different potential mechanisms that cause CRPC, and this has led to the development of novel agents targeting the AR-dependent pathway or AR-independent signaling. In the present review, the major underlying mechanisms causing CRPC, including several major categories of AR-dependent mechanisms, AR bypass signaling, AR-independent mechanisms and other important hypotheses (including the functions of autophagy, PCa stem cell and microRNAs in CRPC progression), are summarized with retrospective pre-clinical or clinical trials to guide future research and therapy.

Keywords: androgen receptor splice variants; autophagy; castration resistant prostate cancer; mechanism; microRNAs; prostate stem cells.

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Figures

Figure 1.
Figure 1.
(A) Functional domains of the AR. (B) Biology of the androgen receptor signaling pathway. DBD, DNA binding domain; LBD, Ligand binding domain; H, hinge region, AF-1, transcriptional activating function 1; AF-2, transcriptional activating function 2; NLS, nuclear localization signal; NES, nuclear export signal; AR, androgen receptor; DHT, dihydrotestosterone; HSP, heat-shock protein; P, phosphorylation.
Figure 2.
Figure 2.
Functional domains of the AR variants. AR, full length AR wild type; AR-V7, product of alternative splicing, CE; ARv567es, product of altered splicing, exon 5, 6 and 7 skipped during splicing; Q640X, AR with a nonsense mutation leading to a tr-AR of 640 aa; enzymatically cleaved by calpain. AR, androgen receptor; DBD, DNA-binding domain; LBD, ligand-binding domain; PCa, prostate cancer; CE, cryptic exon; tr-AR, truncated AR; AR-V, AR splice variants; NTD, N-terminal domain; HR, hinge region.
Figure 3.
Figure 3.
Androgen receptor-dependent mechanisms of resistance in hormone-sensitive prostate cancer leading to castration-resistance. AR, androgen receptor; wtAR, wild-type AR; AR-V, AR splice variants; mutAR, mutated AR; T, testosterone; DHT, dihydrotestosterone; DHEA, dehydroepiandrosterone; STAT3, signal transducer and activator of transcription 3; MAPK, mitogen-activated protein kinase; HSP, heat-shock protein.
Figure 4.
Figure 4.
Schematic representation of the autophagy pathway.
See this image and copyright information in PMC

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