The Dual Roles of NRF2 in Cancer

NRF2 has been traditionally considered as a tumor suppressor because its cytoprotective functions are deemed to be the main cellular defense mechanism against exogenous and endogenous insults, including xenobiotics and oxidative stress. However, several recent studies demonstrate that hyperactivation of the NRF2 pathway creates an environment that favors the survival of normal as well as malignant cells, protecting them against oxidative stress, chemotherapeutic agents, and radiotherapy. In a rapidly advancing field, this review summarizes some of the known mechanisms by which NRF2 can exert its oncogenic functions, and describes the current status of NRF2 inhibitors, providing a clear rationale for the consideration of NRF2 as a powerful putative therapeutic target in cancer treatment.

TrendsUnder homeostatic conditions, NRF2 activation prevents excessive cellular damage produced by metabolic, xenobiotic, and oxidative stress. NRF2 activation is thus important in cancer chemoprevention.Nrf2-null mice are more prone to develop cancer in response to chemical and physical stimuli (nitrosamine, ultraviolet light, aflatoxin).NRF2 hyperactivation confers several advantages to cancer cells, including protection from apoptosis and senescence, promotion of cell growth, and resistance to chemo- and radiotherapy.In experimental models, Nrf2/Keap1 mutations are present at pre-neoplastic stages.Distinct mechanisms are responsible for NRF2 activation in cancer, including (i) somatic mutations in NRF2 or KEAP1, (ii) epigenetic silencing of the KEAP1 promoter, (iii) microRNA-mediated regulation of NRF2 and KEAP1, (iv) aberrant accumulation of proteins that disrupt the interaction between NRF2 and KEAP1, (v) interaction with other ‘cancer master players’, and (vi) metabolic modifications.