Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

Abstract

Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.

An in vitro redox adaptation model for metastatic prostate cancer: Establishing, characterizing and Cabazitaxel response evaluating

“…However, increasing evidence suggests that ADT can induce oxidative stress by increasing ROS levels or decreasing cellular antioxidant system activity in surviving PC cells, which in turn cause genetic and epigenetic effects in PC. [29][30][31] Increased oxidative stress also causes redox signalling amplification and increases androgen receptor (AR) activation through several mechanisms, including AR overexpression, AR activation by co-regulators, mutation of AR and AR-related proteins, expression of AR splice variants, de novo androgen synthesis, etc. These alterations have pro-survival and anti-apoptotic effects on PC cells, resulting in the development of mCRPC.…”

“…The basic one, androgen deprivation therapy (ADT), is the first line of treatment against advanced PC and is also used as an adjuvant to local treatment in patients with high‐risk diseases. However, increasing evidence suggests that ADT can induce oxidative stress by increasing ROS levels or decreasing cellular antioxidant system activity in surviving PC cells, which in turn cause genetic and epigenetic effects in PC 29–31 . Increased oxidative stress also causes redox signalling amplification and increases androgen receptor (AR) activation through several mechanisms, including AR overexpression, AR activation by co‐regulators, mutation of AR and AR‐related proteins, expression of AR splice variants, de novo androgen synthesis, etc.…”

Knockout of NRF2 triggers prostate cancer cells death through ROS modulation and sensitizes to cisplatin

“…Unexpectedly, in DU145 NKO cells, no alteration was found in ROS content compared to control cells (Figure 5B). The complexity of redox‐regulated pathways in which a network of antioxidant proteins and transcription factors work together to maintain the ideal oxidative environment 23 could have compensated for the loss of NRF2 in DU145 cells.…”

Attenuation of Pancreatic Cancer In Vitro and In Vivo via Modulation of Nrf2 and NF-κB Signaling Pathways by Natural Compounds

“…Some data showed that the anti-cancer activity of phytochemicals involves the influence on many signaling pathways which control cell homeostasis. Interactions among Nrf2, NF-κB, and STAT3 signaling pathways, and their dysregulation, may play a key role in the development of cancer—including pancreatic cancer [ 22 , 43 , 44 , 45 ]—driven by the inflammation process. Signaling pathway NF-κB plays a crucial role in inflammatory response and production of pro-inflammatory molecules, including cytokines and enzymes such as COX-2 [ 46 ].…”