Abstract
Cutaneous squamous cell carcinomas (cSCC) are the most common and highly mutated human malignancies, challenging identification of driver mutations and targeted therapies. Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates a cytoprotective inducible program, which counteracts the damaging effects of solar UV radiation, the main etiological factor in cSCC development. Downregulation of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adaptor protein, which mediates the ubiquitination and proteasomal degradation of Nrf2, has a strong protective effect in a preclinical model of cSCC. However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the carcinogenesis process, including proteins involved in inflammation and DNA damage repair. Here, we generated Keap1flox/flox SKH-1 hairless mice in which Nrf2 is disrupted (Keap1flox/flox/Nrf2−/−) and subjected them chronically to solar-simulated UV radiation. We found that the incidence, multiplicity and burden of cSCC that form in Keap1flox/flox/Nrf2−/− mice are much greater than in their Keap1flox/flox/Nrf2+/+ counterparts, establishing Nrf2 activation as the protection mediator. Our findings further imply that inhibition of Nrf2 globally, a strategy proposed for cancer treatment, is unlikely to be beneficial.
Highlights
Inducers)[10,11], which inhibit the substrate adaptor function of Keap[1], leading to Nrf[2] activation, and have shown protective effects in numerous animal models of disease, including cSCC12,13
We have recently developed a mouse model of solar-simulated UV (SSUV) radiation-induced Cutaneous squamous cell carcinomas (cSCC), in which the murine tumors closely resemble the histopathological spectrum of human cSCC13
It was important to ask whether or not Nrf[2] is the mediator of the protective effect of the Keap[1] downregulation that was observed in the SSUV-induced skin carcinogenesis model
Summary
Inducers)[10,11], which inhibit the substrate adaptor function of Keap[1], leading to Nrf[2] activation, and have shown protective effects in numerous animal models of disease, including cSCC12,13. It was important to ask whether or not Nrf[2] is the mediator of the protective effect of the Keap[1] downregulation that was observed in the SSUV-induced skin carcinogenesis model.
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