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

Abstract

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.

In Silico Analysis Validates Proteomic Findings of Formalin-fixed Paraffin Embedded Cutaneous Squamous Cell Carcinoma Tissue

“…The role of KRT9, KRT10, FLG and FLG2 in pathophysiology of human cSCC is not well understood, however KRT10 has been reported to act as skin epithelial tumor suppressor in vivo, primarily through reducing the activity of serine-threonine protein kinase (AKT) and consequently the expression of cyclin D1 (CCND1) (70). AKT is a member of the phosphoinositide 3-kinase (PI3K)/AKT pathway and its activation in response to factors such as overexpression of EGF and its receptor (EGFR) has been reported during skin tumorigenesis (71)(72)(73)(74)(75). Interestingly, in line with previous studies (76), our IPA analysis predicted that EGF is activated in cSCC, which, together with the decrease in KRT10, suggest the potential role of the PI3K/AKT pathway in cSCC carcinogenesis.…”

Molecular signaling cascades involved in nonmelanoma skin carcinogenesis

“…Activation of RAF/MEK/ERK signaling also occurs downstream of EGFR in response to UVR exposure [196, 197], and this pathway has been identified as a chemoprevention target in NMSC [2, 198]. Following EGFR activation (Figure 4B), the growth factor receptor-bound protein 2 (GRB2) is recruited to the receptor, resulting in binding to the guanine nucleotide exchange factor Son of Sevenless (SOS).…”

Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin

“…Phosphoinositide3-kinase (PI3K)/Akt/mTOR signaling is known to be dysregulated in several types of cancer, making the pathway a promising therapeutic target [9]. We and others have shown that UV light exposure induces PI3K/Akt/mTOR signaling along with mitogen activated protein kinases (MAPK) signaling in model systems and in human skin [10–15]. Dysregulation of PI3Kinase/Akt/mTOR signaling during the progression from normal skin to SCC has also been validated [16, 17].…”