Abstract
Ultraviolet radiation is an important etiologic factor in skin cancer and a better understanding of how solar stimulated light (SSL) affects signal transduction pathways in human skin which is needed in further understanding activated networks that could be targeted for skin cancer prevention. We utilized Reverse Phase Protein Microarray Analysis (RPPA), a powerful technology that allows for broad-scale and quantitative measurement of the activation/phosphorylation state of hundreds of key signaling proteins and protein pathways in sun-protected skin after an acute dose of two minimal erythema dose (MED) of SSL. RPPA analysis was used to map the altered cell signaling networks resulting from acute doses of solar simulated radiation (SSL). To that end, we exposed sun-protected skin in volunteers to acute doses of two MED of SSL and collected biopsies pre-SSL and post-SSL irradiation. Frozen biopsies were subjected to laser capture microdissection (LCM) and then assessed by RPPA. The activation/phosphorylation or total levels of 128 key signaling proteins and drug targets were selected for statistical analysis. Coordinate network-based analysis was performed on specific signaling pathways that included the PI3k/Akt/mTOR and Ras/Raf/MEK/ERK pathways. Overall, we found early and sustained activation of the PI3K-AKT-mTOR and MAPK pathways. Cell death and apoptosis-related proteins were activated at 5 and 24 h. Ultimately, expression profile patterns of phosphorylated proteins in the epidermal growth factor receptor(EGFR), AKT, mTOR, and other relevant pathways may be used to determine pharmacodynamic activity of new and selective topical chemoprevention agents administered in a test area exposed to SSL to determine drug-induced attenuation or reversal of skin carcinogenesis pathways.
Highlights
Skin cancer, which includes both nonmelanoma skin cancers (NMSC) and melanoma, is the most common malignancy in the United States and its incidence is rapidly increasing.[1, 2] Skin cancer represents a significant public health and economic burden estimated to be over 8.1 billion dollars annually[3] and consists of 75–80% basal cell carcinomas (BCC) and approximately 18% cutaneous squamous cell carcinomas (SCC)
We utilized Reverse Phase Protein Microarray Analysis (RPPA), a powerful proteomics platform that provides for the broad-scale and quantitative measurement of the activation/phosphorylation state of dozens to hundreds of proteins at once from a single input sample
We used RPPA to interrogate the activation of more than 100 specific total proteins and phosphoproteins that comprised key signaling “hubs” in known cancer pathways that are causally involved in growth and mitogenesis, survival, motility, apoptosis, autophagy, inflammation and energy metabolism in sun-protected skin after an acute dose of two minimal erythema dose (MED) of solar stimulated light (SSL)
Summary
Skin cancer, which includes both nonmelanoma skin cancers (NMSC) and melanoma, is the most common malignancy in the United States and its incidence is rapidly increasing.[1, 2] Skin cancer represents a significant public health and economic burden estimated to be over 8.1 billion dollars annually[3] and consists of 75–80% basal cell carcinomas (BCC) and approximately 18% cutaneous squamous cell carcinomas (SCC). Phospho-p38 were compared to baseline (no SSL), 42 of these investigated MAPK (T180/Y182) was borderline at 1 h (p = 0.02) but significant at proteins had a p-value of ≤ 0.05, but due to the large number of 5 h (p = 0.001) and 24 h (p = 0.002). All of the Cancer when compared to baseline at 24-hrs (p = 0.03) and had a Landscape (CScape) Protein Pathway Activation Maps (example significant Trend Test (p = 0.005), phospho-BAD (S112) was shown in Fig. 1) are available as Supplemental Figure S1). Compares the 5-min time point to baseline (A, top center), and the Additional proteins showing statistically significant results were. A 94.1% agreement in directional change of expression was identified between these two cohorts, strongly supporting the validity of our findings (Table 2)
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