Nrf2 and NF-κB and Their Concerted Modulation in Cancer Pathogenesis and Progression

Abstract

Reactive oxygen species, produced by oxidative stress, are implicated in the initiation, promotion, and malignant conversion of carcinogenesis through activation/suppression of redox-sensitive transcription factors. NF-E2-related factor 2 (Nrf2) encodes for antioxidant and general cytoprotection genes, while NF-κB regulates the expression of pro-inflammatory genes. A variety of anti-inflammatory or anti-carcinogenic phyto-chemicals suppress NF-κB signalling and activate the Nrf2-ARE pathway. In this review we consider the role of Nrf2 and NF-κB in cancer pathogenesis and progression, focusing on their concerted modulation and potential cross-talk.

Scheme 1

Proposed mechanisms for Nrf2 activation. Under normal homeostatic conditions, Nrf2 is retained in the cytoplasm via its interaction with Keap1 and degraded by proteasome. Oxidative stress causes disulfide bond formation between Cys273and 288 in Keap1 leading to Nrf2 release and nuclear translocation; External stimuli induce activation of protein kinases responsible for Nrf2 Ser40phosphorylation and Keap1 dissociation; Keap1 can undergo nuclear-cytoplasmic shuttling leading to disruption of the ARE/Nrf2 interaction.

Scheme 2

Proposed mechanisms for NF-κB activation. In basal conditions NF-κB is sequestered in the cytoplasm by IκBα. Upon stimulation, IκBα is rapidly phosphorylated at Ser32 and 36 by the IKK complex and degraded by the 26 S proteasome (classical pathway); DNA damage induces CK2 activation that leads to phosphorylation of IκBα at Ser293 and proteasome degradation (atypical pathway); oxidative stress induces Syk protein tyrosine kinase activation leading to IkBα Tyr42 phosphorylation and proteasome degradation (Oxidative stress-induced pathway). The released NF-κB dimer translocates to the nucleus and activates target genes by binding with high affinity to κB elements. External stimuli induce NIK and IKKα-dependent proteasomal processing of p100 into p52, which translocates to the nucleus and binds to DNA in association with RelB (alternative pathway).

Scheme 3

Proposed cross-talk between Nrf2 and NF-κB. Nrf-2 activation induces intracellular events that concur to NF-κB suppression and vice versa; MAPK family contributes to the concerted modulation of Nrf2 and NF-κB Green lines: induced events; red lines: resulting inhibitory events; black lines: concerted modulation.