Activation of the PI3K/Akt/mTOR and MAP kinase Signaling Pathways in Response to Acute Solar Simulated Light Exposure of Human Skin

The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8B in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5-minute, 1-, 5-, and 24-hour post SSL. Within the PI3K/Akt pathway, we found activation of Akt (Serine473) to be significantly increased at 5 hrs while mTOR (Serine2448) was strongly activated early and was sustained over 24-hour post SSL. Downstream we observed a marked and sustained increase in phospho-S6 (Serine235/S236) whereas phospho-4E-BP1 (Threonines37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (Threonine180/Tyrosine182) peaked at 1–5 hrs. ERK 1/2 was observed to be immediate and sustained post-SSL. Phosphorylation of histone H3 (Serine10), a core structural protein of the nucleosome, peaked at 5-hour post SSL. The expression of both p53 and COX-2 was increased at 5-hour and was maximal at 24-hour post SSL. Apoptosis was significantly increased at 24 hrs as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers.