Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase

Kawasumi, Masaoki; Lemos, Bianca; Bradner, James E.; Thibodeau, Renee; Kim, Yong-son; Schmidt, Miranda; Higgins, Erin; Koo, Sang-wahn; Angle-Zahn, Aimee; Chen, Adam; Levine, Douglas; Nguyen, Lynh; Heffernan, Timothy P.; Longo, Isabel; Mandinova, Anna; Lu, Yao-Ping; Conney, Allan H.; Nghiem, Paul

Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases inseveral types of cancer, including highly prevalent UV-associated skin carcinomas. The mechanism by which caffeine protectsagainst skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activatedby DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currentlyin clinical trials. Conversely, inhibition of other DNA damage response pathways, such as ataxia telangiectasia mutated (ATM)and BRCA1, promotes cancer. To determine the effect of replication checkpoint inhibition on carcinogenesis, we generated transgenicmice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc?/?. Unlike caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viableand showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylationand twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained tumor-free for significantly longer (P = 0.003) and had 69% fewer tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replicationcheckpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protectiveeffect of caffeinated beverage intake in human epidemiologic studies.