Effect of Caffeine on the ATR/Chk1 Pathway in the Epidermis of UVB-Irradiated Mice

Lü, Yao; Lou, You-Rong; Peng, Qiwei; Xie, Junshan; Nghiem, Paul; Conney, Allan H.

doi:10.1158/0008-5472.can-07-5955

Cited by 61 publications

(61 citation statements)

References 32 publications

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“…Recently, it was shown that both siRNA-triggered inhibition of CHK1 expression as well as caffeine-mediated inhibition of CHK1 activation abrogated checkpoint control and augmented UVB-induced apoptosis in human primary KC. 52 Accordingly, pre-exposure of SKH-1 hairless mice to caffeine resulted in an enhanced rate of UVB-induced apoptosis in the epidermis 53 and protected the animals against photocarcinogenesis. 54 In addition, epidemiological data imply that daily caffeinated coffee consumption decreases the incidence and prevalence of NMSC in Caucasians, 55,56 indicating that CHK1 inhibition is indeed effective in terms of cancer chemoprevention in humans.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

et al. 2013

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Exposure of keratinocytes (KC) to ultraviolet (UV) radiation results in the initiation of apoptosis, a protective mechanism that eliminates cells harboring irreparable DNA damage. Hence, a manipulation of UV-induced apoptosis may significantly influence photocarcinogenesis. We have discovered that the aryl hydrocarbon receptor (AHR), a key regulator of drug metabolism and an UVB-sensitive transcription factor, serves an anti-apoptotic function in UVB-irradiated human KC. Chemical and shRNA-mediated inhibition of AHR signaling sensitized KC to UVB-induced apoptosis by decreasing the expression of E2F1 and its target gene checkpoint kinase 1 (CHK1). The decreased expression of these cell-cycle regulators was due to an enhanced expression of p27 KIP1 and an associated decrease in phosphorylation of both cyclin-dependent kinase 2 and its substrate molecule retinoblastoma protein. The subsequent inhibition of E2F1 autoregulation and downstream CHK1 expression resulted in an enhanced susceptibility of damaged cells to undergo apoptosis. Accordingly, ectopic overexpression of either E2F1 or CHK1 in AHR-knockdown KC attenuated the observed sensitization to UVB-induced apoptosis. Using an AHR-knockout SKH-1 hairless mouse model, we next demonstrated the physiological relevance of the anti-apoptotic function of AHR. In contrast to their AHR-proficient littermates, the constitutive expression of E2F1 and CHK1 was significantly reduced in the skin of AHR-knockout mice. Accordingly, a single exposure of the animals to UVB resulted in an enhanced cleavage of caspase-3 in the skin of AHR-knockout mice. These results identify for the first time the AHR-E2F1-CHK1 axis as a novel anti-apoptotic pathway in KC, which may represent a suitable target for chemoprevention of non-melanoma skin cancer. With an annual incidence of two to three million new cases worldwide, non-melanoma skin cancer (NMSC) is one of the most frequent forms of cancer in humans (World Health Organization; http://www.who.int/uv/faq/skincancer/en/index1 .html). Typically, NMSCs, such as basal cell and squamous cell carcinomas, occur on sun-exposed areas of the skin, indicating that solar ultraviolet (UV) radiation, especially its UVB part (290-320 nm), is the most important etiological factor. 1,2 In fact, it is well established that UVB radiation gives rise to skin cancer without additional initiators or promoters and thus is a complete carcinogen. 1 Because of the thinning of the ozone layer, the increase in recreational sunbathing and the enhanced usage of UV tanning beds, the incidence of NMSC is expected to increase in future years, 1,2 underscoring the urgent need for novel preventives against UV-induced skin malignancies.When skin is exposed to solar radiation, high-energy UVB photons penetrate into the epidermis and initiate the so-called UVB response. 3 The main trigger of this stress response is the absorbance of UVB rays by DNA, which leads to the generation of highly mutagenic DNA photoproducts. 3,4 In addition, UVB exposure results in the formation...

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Section: Discussionmentioning

confidence: 99%

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

et al. 2013

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“…ATR has higher affinity for DNA in UV-damaged cells than in undamaged cells, and damaged DNA stimulates the kinase activity of ATR significantly more than undamaged DNA (34). Caffeine either directly disrupts the ATR/Chk1 checkpoint pathway (35) or inhibits UV-induced phosphorylation of Chk1 and prematurely increases the number of mitotic cells with cyclin B1 that are likely to go on to apoptosis (5). In human keratinocytes, inhibition of the ATR-Chk1 pathway with caffeine augmented UV-induced apoptosis in a p53-independent manner, whereas other known and plausible targets of caffeine were not found to be involved in the UV response (9).…”

Section: Discussionmentioning

confidence: 99%

“…Animal studies have consistently shown that oral or topical administration of caffeine inhibits SCC development in mice treated with UV light (4)(5)(6)(7)(8). Oral administration of tea inhibited UV-induced carcinogenesis in mice, whereas decaffeinated tea elicited substantially less inhibitory activity, which was restored by caffeine (6).…”

Section: Introductionmentioning

confidence: 99%

Increased Caffeine Intake Is Associated with Reduced Risk of Basal Cell Carcinoma of the Skin

Song

Qureshi²,

Han³

2012

Cancer Research

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Studies in animals suggest that caffeine administration helps prevent squamous cell skin cancer development, but there have been limited epidemiologic studies on the association between caffeine consumption and skin cancer risk. Using data from the Nurses' Health Study and the Health Professionals Follow-up Study, we prospectively examined risks of basal cell carcinoma (BCC, 22,786 cases), squamous cell carcinoma (SCC, 1,953 cases), and melanoma (741 cases) in relation to caffeine intake. Cox proportional hazard models were used to calculate relative risks (RR) and 95% confidence intervals (CI). The amount of caffeine intake from all dietary sources was inversely associated with BCC risk. Compared with the lowest quintile, the highest quintile had the lowest risk (RR, 0.82 in women; 95% CI:,0.77-0.86 and RR, 0.87 in men; 95% CI, 0.81-0.94; P trend < 0.0001 in both). A significant inverse association was also found between caffeinated coffee consumption and BCC risk. Compared with individuals who consumed caffeinated coffee less than 1 cup per month, women who consumed more than 3 cups/d had the lowest risk (RR, 0.79; 95% CI, 0.74-0.85; P trend < 0.0001) and the RR for men was 0.90 (95% CI, 0.80-1.01; P trend ¼ 0.003). Caffeine from other dietary sources (tea, cola, and chocolate) was also inversely associated with BCC risk. Decaffeinated coffee consumption was not associated with a similar decrease in BCC risk. In contrast, caffeine intake was not found to be inversely associated with risks of SCC or melanoma. Our findings argue that caffeine intake in men and women is inversely associated with risk of BCC. Cancer Res; 72(13); 3282-9. Ó2012 AACR.

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“…2). Similar to wildtype MEFs, KCs are highly sensitive to caffeine treatment after UV irradiation (46,47). Thus, KCs lacking PKC␦, such as in squamous papillomas and carcinomas, are also likely to have this dual defect in the response to DNA damage, resulting in both reduced cell cycle arrest and reduced apoptosis (23,24,48).…”

Section: Discussionmentioning

confidence: 99%

The Protein Kinase Cδ Catalytic Fragment Is Critical for Maintenance of the G2/M DNA Damage Checkpoint

LaGory

Sitailo

Denning

2010

Journal of Biological Chemistry

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Protein kinase C␦ (PKC␦) is an essential component of the intrinsic apoptotic program. Following DNA damage, such as exposure to UV radiation, PKC␦ is cleaved in a caspase-dependent manner, generating a constitutively active catalytic fragment (PKC␦-cat), which is necessary and sufficient for keratinocyte apoptosis. We found that in addition to inducing apoptosis, expression of PKC␦-cat caused a pronounced G 2 /M cell cycle arrest in both primary human keratinocytes and immortalized

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Effect of Caffeine on the ATR/Chk1 Pathway in the Epidermis of UVB-Irradiated Mice

Cited by 61 publications

References 32 publications

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

Increased Caffeine Intake Is Associated with Reduced Risk of Basal Cell Carcinoma of the Skin

The Protein Kinase Cδ Catalytic Fragment Is Critical for Maintenance of the G2/M DNA Damage Checkpoint

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