Over two million new cases of UV-induced non-melanoma skin cancer are diagnosed yearly in the USA, making it the most common form of cancer in this country. Apigenin, a nonmutagenic, naturally occurring flavonoid found in a variety of fruits and leafy vegetables, inhibits UV-induced skin cancer in mice. Our laboratory and others have shown that apigenin treatment of cells results in a wide variety of antitumorigenic and chemopreventive actions, including suppression of COX-2 expression, enhancement of p53 expression, and induction of cell cycle arrest and apoptosis. However, the primary target(s) responsible for apigenin's chemopreventive function remains elusive. For the first time, we have demonstrated that apigenin activated AMP-activated protein kinase (AMPK) in keratinocytes (mouse and human keratinocyte cell lines, primary normal human epidermal keratinocytes (NHEKs) and mouse epidermis in vivo). The activation of AMPK resulted in inhibition of mTOR signaling, which relieved the block to the autophagy pathway, further inducing autophagy in human keratinocytes. At early stages of tumorigenesis, autophagy acts as a tumor suppressor by removing damaged organelles, proteins, reducing chromosome instability, and inducing type II programmed cell death. Therefore, pharmacological induction of autophagy provides a new strategy for cancer chemoprevention. We have further demonstrated that UV radiation also induced moderate AMPK activation, suggesting that there is a protective cellular response after UV radiation alone, providing limited protection through modest AMPK activation. More intriguingly, pretreatment of keratinocytes or skin with apigenin prior to UV radiation induced AMPK activation dramatically (both in vitro and in vivo). In addition, UV markedly increased mTOR phosphorylation in SKH-1 mice epidermis, and apigenin completely inhibited UV-mediated mTOR activation. Taken together, our results demonstrate that the AMPK/mTOR axis is involved in chemoprevention of UV-induced skin cancer by apigenin, and mechanistically the activation of AMPK further induces autophagy to suppress UV-induced tumorigenesis. Identifying AMPK-mTOR axis as a key target of apigenin and targeting the autophagy pathway for cancer chemoprevention would provide a new target and strategy for the development of better treatment and prevention of skin cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1587. doi:1538-7445.AM2012-1587