Targeting Crosstalk between Nrf-2, NF-κB and Androgen Receptor Signaling in Prostate Cancer - Beyond the Abstract
Besides AR signaling, other molecular signaling pathways play a major role in the initiation and progression of PCa because of their ability to cross-talk with AR and thus modulate AR signaling leading to the abnormal expression of AR-regulated genes like prostate-specific antigen (PSA). Therefore, besides focusing on AR signaling in PCa treatment, emphasis also needs to be given on other potential signaling pathways which can interplay with AR. Oxidative stress and inflammation are two of the critical factors involved both in the initiation as well as progression of PCa. ROS (reactive oxygen species) and the associated oxidative stress has not only been linked with the formation of a tumor but also migratory/invasiveness phenotype of the tumor4. ROS by acting as a secondary messenger can regulate various signaling pathways. The levels of ROS generated are significantly higher in PCa cells compared to the normal prostate cells. Also, NAD(P)H oxidase (Nox) systems are a source of extramitochondrial ROS generation in PCa cells and are linked with the malignant phenotype of PCa5. Inhibition of Nox suppresses proliferation and regulated the activation of several growth signaling pathways like extracellular signal-regulated kinase (ERK)1/ERK2, p38 mitogen-activated protein kinase and AKT protein kinase B besides causing cyclin B-dependent G (2)-M cell cycle arrest.
Nrf2 is a nuclear transcription factor which gets activated in response to oxidative stress. It controls the basal as well as inducible expression of several antioxidant and detoxification enzymes and is indeed the most critical defense pathway used by cells against oxidative stress. Nrf2 has been shown to inhibit the growth as well as the migration of PCa cells by upregulating ferroportin6.
Besides oxidative stress, chronic inflammation leads to the initiation and progression of PCa by modifying the microenvironment of the tumor resulting in the remodeling of extracellular matrix and initiation of epithelial mesenchymal transition7. The chronically inflamed cells release cytokines which command metastatic tumor growth promoting constitutively active stroma. There is a correlation of inflammation with augmented development of risk factor lesions or proliferative inflammatory atrophy in PCa. This is corroborated by the fact that chronic inflammation in benign prostate biopsy specimens has been linked with high-grade prostate tumors in adjoining areas. NF-κB is a crucial link between inflammation and cancer because of its ability to upregulate the expression of tumor stimulating cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) as well as survival genes such as Bcl-extra-large (Bcl-xL)8.
Potential functional cross-talk between Nrf-2 and NF-κB pathways has been documented in the initiation and progression of cancer9. ROS produced by inflammatory cells is one of the chief factors by which chronic inflammation leads to cancer. This is further validated by the fact that Nrf-2 intermediated anti-cancer effect is not only attained by the upregulation of antioxidant machinery but also by the inhibition of pro-inflammatory pathways facilitated by NF-κB signaling. Also, NF-κB activity can be aggravated by lack of Nrf-2 resulting in the increased production of cytokines10.
Conclusion
Potential cross-talk between AR, Nrf-2 and NF-κB plays a major role not only in the initiation of PCa but also its transition to CRPC. Nrf-2 suppresses transactivation of AR by stimulating the nuclear accumulation of p120-Nrf111 whereas NF-κB activates AR signaling by upregulating mRNA, protein as well as transactivation of AR12. The anti-cancer efficacy of phytochemicals like sulforaphane and curcumin in PCa is majorly attributed to the activation of Nrf-213,14 inhibition of NF- κB15,16 and downregulation of AR signaling17,18. Targeting cross-talk between Nrf-2, NF- κB and AR signaling pathways thus can be useful in the chemoprevention of PCa both at the initial as well as the later stage.
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Written by: Namrata Khurana, PhD1 and Suresh C. Sikka, HCLD,CC (ABB) 2
1. Department of Internal Medicine-Medical Oncology, Washington University in St. Louis Medical Campus, St. Louis, Missouri
2. Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana
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