Chk2 as a target for regulating senescence in skin neoplasia

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DESCRIPTION (provided by applicant): Non-melanoma skin cancers (NMSCs) occur more frequently in the human population than any other type of malignancy. The exposure of skin to solar ultraviolet B (UVB) radiation causes DNA damage, most notably mutations in the p53 tumor suppressor gene, which is considered to be the initiating event for the development of NMSCs. The checkpoint kinase, Chk2, is a key DNA damage signal transducer that has been shown to operate in cooperation with p53. The mutations in Chk2 predispose humans to various epithelial cancers. Similarly, in murine skin, Chk2 deficiency augments resistance to ionizing radiation and results in the increased formation of skin tumors in a chemical carcinogenesis protocol. The implementation of cell cycle arrest is a particularly important event that allows the cells to repair damaged DNA before resuming cell cycle progression. Chk2 has recently been shown to be involved in senescence, a state of terminal and irreversible growth arrest. Senescence is a potent anti-carcinogenic program. Most conventional chemo/radiation modalities of cancer treatment that induce cells to undergo apoptosis are often known to induce senescence in cancer cells. However, the mechanisms of the senescence in the tumor cell environment remain to be determined. Identifying both the synthetic and natural compounds that can induce the senescence program in cancer cells, and determining the mechanisms involved in senescent induction in tumor cells, will be important in broadening the range of cancer prevention and treatment options. Our preliminary results show that resveratrol, a phytoalexin derived from the skin of grapes increases Chk2, followed by the induction of senescence. We also show that resveratrol-mediated, p53-independent induction of p21CIP1 and p27KIP1 precedes the occurrence of senescence. We will test the hypothesis that resveratrol acts as a senescence inducer in a p53-independent manner through the modulation of Chk2>p21CIP1/p27KIP1 signaling, and this pathway significantly contributes to the resveratrol-mediated inhibition of UVB-induced skin cancers. We formulated two specific aims to test our hypothesis: the studies in Aim 1 will define the role of Chk2 in resveratrol-mediated senescence and demonstrate the importance of p21/CIP1 and p27KIP1; and the studies in Aim 2 will define the molecular signaling that leads to resveratrol-induced senescence in p53 null murine skin keratinocytes and its contribution to the prevention of UVB-induced skin carcinogenesis.