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

Abstract

Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of cancer, including highly prevalent UV-associated skin carcinomas. The mechanism by which caffeine protects against skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activated by DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase 1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in 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 transgenic mice 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 viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and 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 replication checkpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies.skin cancer prevention | squamous cell carcinoma | xeroderma pigmentosum M ultiple human epidemiologic studies have revealed that coffee or tea intake decreases the risk of UV-associated nonmelanoma skin cancers (1-4) and non-UV-associated cancers, most prominently hepatocellular and endometrial cancers (5). In the largest study, among 93,676 women, each daily cup of caffeinated coffee consumption was dose-dependently associated with a 5% reduction in the prevalence of nonmelanoma skin cancers, whereas decaffeinated coffee had no effect, and tea had an intermediate effect, consistent with its caffeine content (3). These observations in humans hold true in multiple related studies in mice. Oral intake of caffeine in the drinking water of chronically irradiated SKH-1 hairless mice suppressed UVinduced skin cancer development (6). Topical application of caffeine in UV-pretreated "high-risk" mice also inhibited UVinduced squamous cell carcinomas (SCCs) in hairless mice by 72% (7).UV-induced skin tumor development is a complex, long-term pathological process in vivo, and it is unclear how caffeine sup-

Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR

“…Recent reports agree with this conclusion, which appears to apply to a variety of malignancies (50)(51)(52). Although the cancer-selective attributes of ATR inhibition are highly encouraging, caution is certainly warranted when the therapeutic window is narrowed both by the general toxicity produced from high levels of inhibition and the risk of therapyrelated cancers that may result from lower levels of inhibition ( Figure 6).…”

Inhibition of ATR-Dependent Signaling by Protoapigenone and Its Derivative Sensitizes Cancer Cells to Interstrand Cross-link–Generating Agents In Vitro and In Vivo

“…However, there is no known cancer associated with ATR gene alterations. Specific ATR inhibition by expression of kinase-inactive ATR specifically in the skin prevents UV-induced skin carcinogenesis (44), suggesting that ATR inhibition has chemopreventive effects on nontransformed cells. Conversely, ATR has been proposed to play a critical role in directing cell death by senescence in unperturbed cells, where ATR is activated by overexpression of the oncoprotein Mos or the ATR activator TopBP1, respectively (45,46).…”

A Novel Topical Targeting System of Caffeine Microemulsion for Inhibiting UVB-Induced Skin Tumor: Characterization, Optimization, and Evaluation

“…CAF has demonstrated an inhibitory effect on UV-induced skin carcinogenesis by functioning as a sunscreen and a stimulatory effect on apoptosis in the epidermis of UVB-treated mice (2,3,(5)(6)(7)(8). Lu et al have proved that topical application of CAF selectively induced apoptosis in tumor without affecting neighboring nontumor site (9).…”

“…However, regulation of apoptosis has been proved to be one relevant factor in UV carcinogenesis. In fact, apoptosis inhibitor expressed in transgenic mice could accelerate the development of UV-induced squamous cell carcinomas (3).…”