Targeting Crosstalk between Nrf-2, NF-κB and Androgen Receptor Signaling in Prostate Cancer

Abstract

Oxidative stress, inflammation and androgen receptor (AR) signaling play a pivotal role in the initiation, development and progression of prostate cancer (PCa). Numerous papers in the literature have documented the interconnection between oxidative stress and inflammation; and how antioxidants can combat the inflammation. It has been shown in the literature that both oxidative stress and inflammation regulate AR, the key receptor involved in the transition of PCa to castration resistant prostate cancer (CRPC). In this review, we discuss about the importance of targeting Nrf-2-antioxidant signaling, NF-κB inflammatory response and AR signaling in PCa. Finally, we discuss about the crosstalk between these three critical pathways as well as how the anti-inflammatory antioxidant phytochemicals like sulforaphane (SFN) and curcumin (CUR), which can also target AR, can be ideal candidates in the chemoprevention of PCa.

Keywords: AR-V7; NF-κB; Nrf-2; androgen receptor (AR); castration resistant prostate cancer (CRPC); curcumin and bardoxolone methyl; inflammation; oxidative stress; prostate cancer; sulforaphane.

Figure 1

Crosstalk between Nrf-2, NF-κB and AR in PCa: Oxidative stress leads to inflammation and vice versa. Oxidative stress results in the activation and nuclear localization of Nrf-2 after its dissociation from Keap1. Nrf-2 after localizing to the nucleus binds to the antioxidant response elements leading to the transcription and translation of antioxidant proteins. Inflammation, on the other hand, leads to the activation and nuclear localization of NF-κB after its dissociation from IκB, where it binds to NF-κB response elements leading to the transcription and translation of inflammatory proteins. Nrf2 signaling inhibits NF-κB signaling and vice versa. On the other hand, Nrf-2 inhibits AR whereas NF-κB activates AR signaling. AR after binding to androgens dissociates from HSPs (heat shock proteins), translocates to the nucleus leading to the transcription and translation of AR regulated proteins like prostate specific antigen (PSA).

Figure 2

Multiple effects of SFN/CUR: SFN/CUR shows its anti-cancer effect in PCa by activation of Nrf-2 signaling and inhibition of NF-κB as well as AR signaling. As these three pathways are interlinked with each other, it leads to the upregulation of antioxidant proteins and downregulation of inflammatory proteins eventually resulting in the overall suppression of AR signaling and PCa growth.