Role of AMPK in UVB-induced DNA damage repair and growth control

Abstract

Skin cancer is the most common cancer in the U.S., while DNA-damaging UVB radiation from the sun remains the major environmental risk factor. Reducing skin cancer incidence is becoming an urgent issue. The energy-sensing enzyme 5’-AMP-activated protein kinase (AMPK) plays a key role in the regulation of cellular lipid and protein metabolism in response to stimuli such as exercise and changes in fuel availability. However, the role AMPK in the response of skin cells to UVB damage and in skin cancer prevention remains unknown. Here we show that AMPK activation is reduced in human and mouse squamous cell carcinoma as compared with normal skin, and by UVB irradiation, suggesting that AMPK is a tumor suppressor. At the molecular level, AMPK deletion reduced the expression of the DNA repair protein xeroderma pigmentosum C (XPC) and UVB-induced DNA repair. AMPK activation by its activators AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) and metformin (N’,N’-dimethylbiguanide), the most widely used anti-diabetic drug, increased the expression of XPC expression and UVB-induced DNA repair in mouse skin, normal human epidermal keratinocytes, and AMPK wild-type cells but not in AMPK deficient cells, indicating an AMPK-dependent mechanism. Topical treatment with AICAR and metformin not only delayed onset of UVB-induced skin tumorigenesis but also reduced tumor multiplicity. Furthermore, AMPK deletion increased ERK activation and cell proliferation, while AICAR and metformin inhibited ERK activation and cell proliferation in keratinocytes, mouse skin, AMPK wild-type and AMPK deficient cells, suggesting an AMPK-independent mechanism. Finally, in UVB-damaged tumor-bearing mice, both topical and systemic metformin prevented the formation of new tumors and suppressed growth of established tumors. Our findings not only suggest that AMPK is a tumor suppressor in the skin by promoting DNA repair and controlling cell proliferation, but also demonstrate previously unknown mechanisms by which the AMPK activators prevent UVB-induced skin tumorigenesis.

Dual role of SIRT1 in UVB-induced skin tumorigenesis

“…Frozen tissues were obtained under consent at the Section of Dermatology, Department of Medicine, University of Chicago as in our previous studies (46). …”

Sestrin2 Protein Positively Regulates AKT Enzyme Signaling and Survival in Human Squamous Cell Carcinoma and Melanoma Cells

“…In Vitro Cell Proliferation Assay-Cell proliferation of A431 and A375 stable cells was analyzed using the MTS assay (Promega, Madison, WI) according to the manufacturer's instructions as in our recent studies (21). The BrdU assay was monitored using a cell proliferation ELISA BrdU (colorimetric, Roche Applied Science) kit according to the manufacturer's instructions as in our previous studies (26).…”

AMPKα1 deficiency promotes cellular proliferation and DNA damage via p21 reduction in mouse embryonic fibroblasts

“…Emerging data indicate that AMPK plays an important role in tumor suppression [24, 25]. It was recently reported that AMPK regulates UVB-induced DNA damage repair in skin tumor cells [26], as well as playing a role in NHEJ via the LKB1-AMPK signaling pathway [27]. However, the exact role of the two AMPKα isoforms and the mechanism by which AMPK might control the cell cycle and DNA damage remain elusive.…”