Non-melanoma skin cancer (NMSC) is the most common type of cancer in the US, with more than one million new cases of skin cancer being diagnosed each year, accounting for 40% of all newly diagnosed cancer cases. The number of NMSC continues to rise each year. The major risk factor for NMSC is environmental UV radiation, in which UVB in sunlight is the dominant skin carcinogen (1
). UVB damages DNA, causes somatic mutations, and thus disrupts genomic integrity.
The predominant DNA photoproducts caused by UVB radiation are pyrimidine(6-4)pyrimidone dimers (6-4PP) and cyclobutane pyrimidine dimers (CPD) (4
). CPD are also a major source of DNA breaks (6
) that cause genomic instability (7
). Replication of damaged DNA can cause mutations that may ultimately lead to skin carcinogenesis (8
). In response to DNA damage, the cells activate a specific DNA repair mechanism, global genome nucleotide excision repair (GG-NER), which involves well-coordinated actions of DNA damage-binding proteins 1 and 2 (DDB1 and DDB2) and the xeroderma pigmentosum (XP) proteins (XPA-G) (11
). A deficiency in repairing UV-induced DNA damage substantially accelerates skin cancer development, as seen in xeroderma pigmentosum (XP) patients with genetic defects in the repair of UV-induced DNA damage (11
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, and is conserved among animals, plants, and fungi (19
). AMPK is a heterotrimer that contains α-, β-, and γ-subunits, each of which has at least two isoforms. Emerging evidence indicates that AMPK is a promising metabolic tumor suppressor and a target for cancer prevention and therapy (21
). The AMPK pathway intersects with the oncogenic Ras/PI3K/mTOR and ERK pathways at multiple points in growth control pathways (19
). AMPK signaling also interacts with the p53 and ATM pathways, two essential tumor suppressors and genomic gatekeepers, to coordinate metabolic checkpoints and DNA damage response (22
). As more functions and targets of AMPK are decoded, the challenge will be in determining the role of AMPK activity in malignancies and the precise interactions of AMPK with a specific organ and its carcinogenic causes. These future findings will provide a fundamental basis for AMPK activators as new agents and for strategies to better prevent and treat cancer.
There are two AMPK activators that have been explored for cancer treatment. One of them is the most widely used anti-diabetic drug, metformin (N’,N’-dimethylbiguanide), which belongs to the biguanide class of oral hypoglycemic agents. It is now prescribed to almost 120 million people worldwide and has become the first line anti-hyperglycemic agent in the treatment of type 2 diabetes (25
). Metformin works mainly by activating the AMPK pathway and via an AMPK-independent mechanism (26
). Retrospective studies suggest that diabetics treated with metformin have a substantially reduced cancer burden compared with other diabetics. It is unclear whether this reflects a chemopreventive effect, and whether these data have relevance to people without diabetes. Over the past few years, however, impressive evidence from several studies indicates that metformin exhibits cancer prevention effects in vitro
and in animal models (28
). In addition, another AMPK activator, AICAR (5-aminoimidazole-4-carboxamide ribonucleoside), has been shown to suppress glioblastoma growth in vivo
) and melanoma cell growth in vitro
). AICAR also inhibits keratinocyte growth in vitro
). However, the role AMPK in the response of skin cells to UVB and in skin cancer prevention remains unknown.
Here we have investigated the role of AMPK in UVB-induced DNA damage repair and cell proliferation, two critical processes determining skin cancer susceptibility, and the impact of AICAR and metformin on UVB-induced skin tumorigenesis and the role of AMPK activation. We found that the activation of the energy-sensing enzyme 5’-AMP-activated protein kinase (AMPK) was reduced in human and mouse squamous cell carcinomas as compared with normal skin and by UVB damage. AMPK plays important roles in UVB-induced DNA damage repair and cell growth. Both AICAR and metformin reduced UVB-induced skin tumorigenesis. Furthermore, both topical and systemic metformin inhibited growth of established tumors and prevented new tumor formation in mice with previous UVB damage. At the molecular level, bothAMPK-dependent- and independent-mechanisms are involved.