The Dual Roles of NRF2 in Cancer

Under 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. 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. 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. a carcinogenic mycotoxin produced by fungi (mainly Aspergillus) that causes mutations through binding of its metabolites to DNA. nutrient generated from vitamin A that helps cells to grow and develop, especially in the embryo. ATRA binds to and activates retinoic acid receptors (RARs), thereby inducing changes in gene expression that lead to cell differentiation and decreased cell proliferation. natural, destructive mechanism that disassembles, through a regulated process, unnecessary or dysfunctional cellular components. Autophagy allows the orderly degradation and recycling of cellular components. B-RAF encodes a serine/threonine protein kinase that is part of the RAS–MAPK signaling cascade. the use of natural, synthetic, or biological substances, food supplements, or other agents in the diet to inhibit the development or progression of malignant changes in cells. short stretches of DNA in which the frequency of the CG sequence is higher than in other regions. The ‘p’ in CpG indicates that ‘C’ and ‘G’ are connected by a phosphodiester bond. represses transcription when tethered to a promoter and plays a key role in transcriptional regulation, cell cycle progression, and developmental events. c-JUN, in combination with c-FOS, forms the AP-1 early response transcription factor. MYC is a transcription factor that activates expression of many genes through binding enhancer box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). a GTPase that recruits and activates proteins, such as c-RAF and PI3K, that are necessary for the propagation of receptor signals. an imbalance between the generation of reactive oxygen metabolites (free radicals) and antioxidant defense mechanisms. a metabolic pathway parallel to glycolysis that generates NADPH and pentoses as well as ribose 5-phosphate, a precursor of nucleotide synthesis. enzymes engaged in biotransformation (through conjugating reactions of endogenous compounds and xenobiotics to more easily excretable forms), as well as in the metabolic inactivation of pharmacologically active substances. the signaling network defined by PI3K, AKT, and the mechanistic target of rapamycin (mTOR) which controls most hallmarks of cancer. The pathway also contributes to cancer-promoting aspects of the tumor environment such as angiogenesis and inflammatory cell recruitment. a family of protein kinase enzymes involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on those proteins. immature red blood cells (typically 1% of red blood cells in humans) that still harbor some RNAs and mitochondria. a blood disorder due to a genetic alteration of hemoglobin. This leads to rigid, sickle-like shaped dysfunctional erythrocytes. foreign chemicals or natural compounds that include carcinogens, drugs, drug metabolites, and environmental compounds such as pollutants, synthetic pesticides, and herbicides. the phenomenon by which most cancer cells predominantly produce energy by a high rate of glycolysis instead of by mitochondrial pyruvate oxidation as in most normal cells.