Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer.

Namrata Khurana,Suresh C Sikka

doi:10.3390/ijms20092066

Abstract

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

Highlights

Prostate cancer (PCa) is the second cause of cancer in men and the fifth cause of cancer-related mortality in men worldwide [1]
Prostate-specific antigen (PSA) testing is very sensitive for screening patients with abnormal tumor growth, it is not very specific as PSA levels can even increase with the age and size of the prostate gland and does not necessarily confirm a tumor
We recently reported that sulforaphane (SFN), an isothiocyanate derived from broccoli can increase the efficacy of antiandrogens in both androgen-dependent as well as androgen-independent cell lines by degrading both Androgen receptor (AR)-full length (FL) and AR-V7 [31,32]

Summary

Introduction

Prostate cancer (PCa) is the second cause of cancer in men and the fifth cause of cancer-related mortality in men worldwide [1]. Prostate-specific antigen (PSA) testing, along with a digital rectal exam (DRE), was approved by the Food and Drug Administration (FDA) for screening asymptomatic men for PCa [2]. PSA levels in the blood are used for evaluating the effect of cancer treatments and detecting relapse of cancer after initial therapy. PSA testing is very sensitive for screening patients with abnormal tumor growth, it is not very specific as PSA levels can even increase with the age and size of the prostate gland and does not necessarily confirm a tumor. The combination of PSA levels, GS and TNM staging is utilized for evaluating disease burden and results of the treatment therapy [5]. Prostatectomy or surgical removal of the prostate is the most extensively used treatment for early stage PCa when the tumor is limited to prostate [6]. Hormone therapy known as androgen deprivation therapy (ADT) and lastly chemotherapy is given to the patients for whom prostatectomy or radiotherapy fails [7]

Androgen Receptor Signaling in Prostate Cancer

Findings

SOX9 and AR Signaling