Abstract 1260: Mechanism of skin cancer chemoprevention by dietary grape: A global proteomics approach

Abstract

Abstract Non-melanoma skin cancer (NMSC), composed mainly of squamous cell carcinomas (SCC) and basal cell carcinomas (BCC), is the most commonly diagnosed form of cancer in the United States, with more than 5 million cases diagnosed each year. Ultraviolet (UV) radiation, a major component of sunlight, is the primary contributing factor in the development of NMSCs. Based on research in the past few decades, the naturally occurring dietary antioxidants have shown considerable promise towards preventing or delaying the process of carcinogenesis. We have previously demonstrated that dietary grape powder (GP) imparts considerable chemopreventive effects against UVB exposure-mediated skin carcinogenesis in SKH-1 hairless mice (AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5263). Here, we extended our study to determine the molecular mechanisms associated with the observed chemopreventive response of grapes. We employed a quantitative proteomics approach to identify the mechanism of observed protective effects of GP against UVB exposure-mediated skin carcinogenesis. The trypsin-digested protein extracts from UVB exposure-mediated skin tumors excised from control and 5% GP-fed mice were labeled using TMT10plex isobaric mass tagging reagents, fractionated, and analyzed by high-resolution Orbitrap LC-MS/MS. Post-acquisition analysis was performed using MaxQuant and Perseus computational software. We found that approximately 2600 total proteins were modulated by GP consumption. In our first set of data reduction, we used cut-off parameters of a p-value less than 0.05, 3 unique peptides, and greater than 1.2 fold change. A low fold change threshold was selected due to ratio compression, a known phenomenon in isobaric mass tagging which leads to underestimation of quantitative ratios. The resulting subset of 239 proteins were then subjected to Ingenuity Pathway Analysis (IPA), which identified Acute Phase Response (APR), a systemic response to trauma which is linked to poor cancer prognosis when prolonged, as a pathway affected by GP. We observed modulations in nine APR proteins (APCS, HP, RBP1, FGB, FGA, CRABP2, C1S, HPX, IL36G, AMBP). Application of a more stringent data filter (permutation FDR q-value less than 0.07) exposed a subset of 20 proteins. When analyzed by IPA, the results suggested that GP affects signaling proteins associated with the 20s proteasome (PSMA6, PSMA3, and PSMB7) and 19s proteasome (UCHL5), both components of the 26s proteasome signaling, which plays an important role in cancer. Further studies are underway to validate our proteomics data. Citation Format: Charlotte A. Mintie, Chandra K. Singh, Mary A. Ndiaye, Gregory A. Barrett-Wilt, Nihal Ahmad. Mechanism of skin cancer chemoprevention by dietary grape: A global proteomics approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1260.