Abstract
Androgen receptor (AR) signaling is fundamental to prostate cancer (PC) progression, and hence, androgen deprivation therapy (ADT) remains a mainstay of treatment. However, augmented AR signaling via both full length AR (AR-FL) and constitutively active AR splice variants, especially AR-V7, is associated with the recurrence of castration resistant prostate cancer (CRPC). Oxidative stress also plays a crucial role in anti-androgen resistance and CRPC outgrowth. We examined whether a triterpenoid antioxidant drug, Bardoxolone-methyl, known as CDDO-Me or RTA 402, can decrease AR-FL and AR-V7 expression in PC cells. Nanomolar (nM) concentrations of CDDO-Me rapidly downregulated AR-FL in LNCaP and C4-2B cells, and both AR-FL and AR-V7 in CWR22Rv1 (22Rv1) cells. The AR-suppressive effect of CDDO-Me was evident at both the mRNA and protein levels. Mechanistically, acute exposure (2 h) to CDDO-Me increased and long-term exposure (24 h) decreased reactive oxygen species (ROS) levels in cells. This was concomitant with an increase in the anti-oxidant transcription factor, Nrf2. The anti-oxidant N-acetyl cysteine (NAC) could overcome this AR-suppressive effect of CDDO-Me. Co-exposure of PC cells to CDDO-Me enhanced the efficacy of a clinically approved anti-androgen, enzalutamide (ENZ), as evident by decreased cell-viability along with migration and colony forming ability of PC cells. Thus, CDDO-Me which is in several late-stage clinical trials, may be used as an adjunct to ADT in PC patients.
Highlights
Prostate cancer (PC) is the second leading cause of cancer-related mortality in men in the UnitedStates [1]
There is a critical requisite for potential therapeutic strategies which can efficiently reduce androgen receptor (AR)-FL and AR-V7 linked constitutive tumor promoting signaling in the castration-resistant prostate cancer (CRPC) cells
Second messenger signaling via the androgen receptor is indispensable for the prostate epithelial cells, for the normal functioning and homeostasis of the prostate gland and for the Second messenger signaling via the androgen receptor is indispensable for the prostate epithelial cells, for the normal functioning and homeostasis of the prostate gland and for the development of prostatic neoplasms and the progression of prostate cancer (PC) to CRPC [2]
Summary
Prostate cancer (PC) is the second leading cause of cancer-related mortality in men in the United. CRPC cells include AR gene amplification, ligand-independent AR activation by cytokines or kinases, both intracrine and/or intratumoral androgen production, overexpression of AR co-activators, and most importantly, the expression of constitutively active AR splice variants (AR-Vs) [8,9]. Despite the castrated levels of androgens, these spliced forms of AR lacking the C-terminal ligand binding domain (LBD), promote the transcriptional activation of AR target genes as they still retain the transactivating. Activated Nrf reduces intracellular reactive oxygen species (ROS) levels via the transcriptional induction of numerous antioxidant proteins, e.g., superoxide dismutase (SOD) and glutathione peroxidase (GPX) leading to a synchronized antioxidant and anti-inflammatory response [33]. We have shown that at physiologically achievable plasma concentrations (i.e., nanomolar doses) [24], CDDO-Me suppresses gene expression and protein levels of both AR-FL and AR-V7 in the LNCaP, C4-2B, and CWR22Rv1 (22Rv1) cells.
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