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.

Keywords: Nrf2; Nrf2-activators; Prostate cancer; androgen receptor; endocrine resistance; hormone therapy; oxidative stress; redox signaling.

Figure 1

Increased oxidative stress, ROS production and redox signaling during PCa progression. A schematic representation of the prostate gland is shown on the left. Neoplastic transformation of the normal epithelium leads to PIN lesions, which progress to localized adenocarcinoma and depends on androgen and AR signaling for growth. Administration of ADT causes hormone-deprivation-induced oxidative stress, ROS production and amplified redox signaling networks in PCa cells, which facilitates the selection of CRPC cells. These aggressive CRPC cells can then metastasize to distant sites to form mCRPC, which dictates morbidity and mortality in patients. PCa: prostate cancer; ADT: androgen deprivation therapy; ROS: reactive oxygen species; CRPC: castrate resistant prostate cancer; mCRPC: metastatic CRPCs

Figure 2

Signaling via AR occurs by both ligand-dependent and ligand-independent mechanisms. The male steroid hormones, androgen and testosterone (T) are produced by the testes and adrenal glands and manifest their endocrine effects on PCa cells via ligand-dependent activation of AR signaling (left). Inside the PCa cells, T is converted to a highly potent analog dihydrotestosterone (DHT) by the 5α-reductase enzyme. DHT binding to AR releases it from its chaperone, the heat shock proteins (Hsp). The activated AR then dimerizes and translocates to the nucleus, where it recruits coregulators of transcription to increase PCa growth. Ligand-independent activation of AR (right) can also occur due to multiple signaling pathways, primarily activated by inflammatory cytokines, and utilize ROS as second messengers. Therefore, amplified redox signaling networks can facilitate non-AR signaling, resulting in CRPC outgrowth post hormone deprivation. AR: androgen receptor; PCa: prostate cancer; ROS: reactive oxygen species; CRPC: castrate resistant prostate cancer

Figure 3

Multiple signaling cascades are activated following IL-6 binding to its receptor (GP130). Ligand binding causes GP130 dimerization and activation (phosphorylation) of the associated JAK kinase, which then activates downstream STAT transcription factor. GP130 activation can also transduce second messenger signaling via the RAS/RAF/MEK/ERK pathway to activate MAP kinase (MAPK). In addition, this inflammatory cytokine can also initiate the PI3K signaling at the membrane, which can either activate IκB kinase (IKK) and thus enhance NF-κB transcription factor function or PI3K may activate the downstream protein kinase B (AKT) which suppress NF-κB activation. Therefore, IL-6 signaling activates multiple redox signaling networks that may crosstalk with AR and activate it in a ligand-independent manner. IL-6: interleukin-6; JAK: Janus associated kinase; STAT: signal transducers and activators of transcription; NF-κB: nuclear factor kappa B

Figure 4

Crosstalk regulation of Nrf-2, NF-κB and AR signaling in CRPC cells. Hormone deprivation (ADT) induced oxidative stress and redox signaling activates both NF-κB and AR signaling that facilitates CRPC progression. Oxidative stress also increases Nrf2 nuclear levels which blocks both NF-κB and AR signaling. Thus, reduction of oxidative stress post-ADT by using potent Nrf2-activating agents may prevent CRPC outgrowth. CRPC: castrate resistant prostate cancer; NF-κB: nuclear factor kappa B; AR: androgen receptor

Figure 5

Therapeutic potential of Nrf2 activators in suppressing ADT-induced oxidative stress and CRPC progression. Androgen deprivation increases oxidative stress in PCa cells, which causes inflammation and redox signaling amplification in surviving tumor cells. This vicious cycle of signaling crosstalk between AR and non-AR signaling pathways facilitates the selection and outgrowth of CRPC. Potent Nrf2 activators, especially those under clinical trials, may abrogate this vicious cycle and suppress the development of endocrine resistant PCa. CRPC: castrate resistant prostate cancer; AR: androgen receptor; ADT: androgen deprivation therapy