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

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.