Identification of Molecular Targets of Dietary Grape-Mediated Chemoprevention of Ultraviolet B Skin Carcinogenesis: A Comparative Quantitative Proteomics Analysis

Abstract

We recently showed that dietary grape powder (GP) imparts considerable protection against ultraviolet B (UVB)-mediated skin carcinogenesis in SKH-1 mice. To determine molecular mechanisms of this response, we employed tandem mass tag (TMT) quantitative global proteomics approach on skin tumors from mice exposed to 180 mJ/cm2 UVB twice per week and fed control or 5% GP diet. We found 2629 proteins modulated by GP feeding, with 34 identified using stringent cutoffs (false discovery rate (FDR) q-value ≤ 0.1, fold change ≥ 1.2, p-value ≤ 0.05, ≥ 3 unique peptides). Ingenuity Pathway Analysis helped identify seven proteins involved in protein ubiquitination, including the deubiquitinase UCHL5 and 6 subunits of the 20S proteasome (PSMA1,3,4,6 and PSMB4,7). A second data set without the FDR q-value identified 239 modulated proteins, seven of which are involved in protein ubiquitination. Further, 14 proteins involved in acute phase response signaling were modulated >1.5-fold, including acute phase proteins APCS, FGA, FGB, HP, HPX, and RBP1. Evaluation of upstream regulators found inhibition of ERK1/2 phosphorylation and NF-κB p65, and an increase in IκBα in GP-treated tumors. Overall, our data suggested that GP consumption may mitigate tumorigenesis by enhancing protein ubiquitination and degradation caused by oxidative stress, and manipulates an otherwise tumor-promoting anti-inflammatory environment.