Oncogenic functions of the transcription factor Nrf2

Abstract

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that controls the expression of a large pool of antioxidant and cytoprotective genes regulating the cellular response to oxidative and electrophilic stress. Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1) and, upon stimulation by an oxidative or electrophilic insult, is rapidly activated by protein stabilization. Owing to its cytoprotective functions, Nrf2 has been traditionally studied in the field of chemoprevention; however, there is accumulated evidence that Keap1/Nrf2 mutations or unbalanced regulation that leads to overexpression or hyperactivation of Nrf2 may participate in tumorigenesis and be involved in chemoresistance of a wide number of solid cancers and leukemias. In addition to protecting cells from reactive oxygen species, Nrf2 seems to play a direct role in cell growth control and is related to apoptosis-regulating pathways. Moreover, Nrf2 activity is connected with oncogenic kinase pathways, structural proteins, hormonal regulation, other transcription factors, and epigenetic enzymes involved in the pathogenesis of various types of tumors. The aim of this review is to compile and summarize existing knowledge of the oncogenic functions of Nrf2 to provide a solid basis for its potential use as a molecular marker and pharmacological target in cancer.

Keywords: AML; ARE; Apoptosis; Autophagy; C/EBP homologous protein; CHOP; CML; COL; Cancer; Cell growth; Chemoresistance; Cytoprotection; EOC; ER; ERK; ESCC; Electrophiles; Free radicals; GSK-3β; HCC; JNK; Keap1; LC3α; LOH; MAP kinase-ERK kinase; MDR; MEK; MGMT; Mutation; NSCLC; Nrf2; Oxidative stress; PI3K; PKC; PT; Proto-oncogene; SAHA; SCC; STC; Tumorigenesis; acute myeloid leukemia; antioxidant response element; b-ZIP; c-Jun N-terminal kinase; chronic myelogenous leukemia; colorectal carcinoma; epithelial ovarian carcinoma; esophagus squamous cell carcinoma; estrogen receptor; extracellular-regulated MAP kinase; glycogen synthase kinase 3β; hepatocellular carcinoma; kinase light chain 3α; leucine-zipper protein; loss of heterogeneity; mTOR; mammalian target of rapamycin; methylguanine DNA-methyltransferase; multidrug resistance; non-small-cell lung carcinoma; phosphatidylinositol-4, 5-bisphosphate 3-kinase; primary tumor; protein kinase C; squamous cell carcinoma; stomach carcinoma; suberoylanilide hydroxamic acid.