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

Figures

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  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

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  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

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  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

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  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

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  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