Caffeine Promotes Ultraviolet B-induced Apoptosis in Human Keratinocytes without Complete DNA Repair*

In response to ultraviolet B damage, keratinocytes undergo apoptosis to eliminate damaged cells, thereby preventing tumorigenic transformation. Caffeine, the most widely consumed psychoactive substance, produces complex pharmacological actions; it has been shown to be chemopreventive in non-melamona skin cancer in mice through increasing apoptosis. Here we have investigated the molecular and cellular mechanisms in the pro-apoptotic effect of caffeine on UVB-irradiated human HaCaT keratinocytes. Pretreatment with caffeine increased UVB-induced apoptosis in HaCaT cells. Caffeine blocked UVB-induced Chk1 phosphorylation. In addition, similar to the effect of the PI3K inhibitor LY294002, caffeine also inhibited phosphorylation of AKT and up-regulation of COX-2, two critical oncogenic pathways in skin tumorigenesis. However, phosphorylation of EGFR or ERK was unaffected. Inhibiting ATR pathways by siRNA targeting ATR had little effect on UVB-induced apoptosis or AKT activation, indicating that the inhibitory effect of caffeine on apoptosis and the AKT pathway does not require the ATR pathway. Inhibiting AKT by caffeine blocked UVB-induced COX-2 up-regulation. Expression of constitutively active AKT that was not inhibited by caffeine was found to protect cells from caffeine-promoted apoptosis post-UVB irradiation, indicating that AKT is an essential inhibitory target for caffeine to promote apoptosis. Caffeine specifically sensitized cells with unrepaired DNA damage to UVB-induced apoptosis. These findings indicate that in HaCaT keratinocytes, inhibiting the AKT/COX-2 pathways through an ATR-independent pathway is a critical molecular mechanism by which caffeine promotes UVB-induced apoptosis of unrepaired keratinocytes for elimination.

• Publication year

  2011

• Venue

  Journal of Biological Chemistry

• Publication date

  2011-05-11

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1074/jbc.M111.222349PMID 21561856PMCID PMC3123050
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Caffeine specifically sensitizes cells with unrepaired DNA damage to UVB-induced apoptosis.

  Confidence 0.85

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• AKT is an essential inhibitory target for caffeine to promote UVB-induced apoptosis, as constitutively active AKT not inhibited by caffeine protects cells from caffeine-promoted apoptosis post-UVB irradiation.

  Confidence 0.90

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• Caffeine inhibits phosphorylation of AKT and up-regulation of COX-2 in UVB-irradiated HaCaT cells through an ATR-independent pathway.

  Confidence 0.90

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• Pretreatment with caffeine increases UVB-induced apoptosis in HaCaT keratinocytes.

  Confidence 0.95

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review

• akt

  protein, signaling molecule

  A serine/threonine kinase involved in an oncogenic signaling pathway whose phosphorylation is inhibited by caffeine.

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• atr

  protein, kinase

  A kinase involved in the DNA damage response whose pathway was shown to be dispensable for caffeine's effects on apoptosis and AKT.

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• caffeine

  chemical compound

  A widely consumed psychoactive substance investigated here for its pro-apoptotic and chemopreventive effects on UVB-irradiated keratinocytes.

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• chk1

  protein, kinase

  A checkpoint kinase downstream of ATR whose UVB-induced phosphorylation is blocked by caffeine.

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• cox-2

  enzyme

  Cyclooxygenase-2, an enzyme up-regulated by UVB that is part of a critical oncogenic pathway in skin tumorigenesis.

  Aliases: cyclooxygenase-2

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• dna damage

  biological process

  Genomic lesions caused by UVB irradiation that, when unrepaired, sensitize cells to caffeine-promoted apoptosis.

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• hacat keratinocytes

  cell line

  A human keratinocyte cell line used as the experimental model in this study.

  Aliases: HaCaT cells

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review
• uvb-induced apoptosis

  biological process

  Programmed cell death triggered by ultraviolet B radiation to eliminate damaged keratinocytes.

  Aliases: UVB-induced cell death

  --------- ✂ Cut Here ✂ --------- (jqthcshryb) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) reviewAll you need is Python (5d7gwfm5zu) review

• Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

  2010cited by this paper
• Immunosuppressive Cyclosporin A Activates AKT in Keratinocytes through PTEN Suppression

  2010cited by this paper
• Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C

  2010cited by this paper
• ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes: potential basis for the UV protective effects of caffeine.

  2009cited by this paper
• Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity

  2009cited by this paper
• UVB induced ERK/AKT-dependent PTEN suppression promotes survival of epidermal keratinocytes

  2009cited by this paper
• ATR kinase is required for global genomic nucleotide excision repair exclusively during S phase in human cells

  2008cited by this paper
• Early Events in UV Carcinogenesis—DNA Damage, Target Cells and Mutant p53 Foci †

  2008cited by this paper
• ATR: an essential regulator of genome integrity

  2008cited by this paper
• Effect of caffeine on the ATR/Chk1 pathway in the epidermis of UVB-irradiated mice.

  2008cited by this paper
• Cyclooxygenase‐2 expression is critical for chronic UV‐induced murine skin carcinogenesis

  2007cited by this paper
• Cyclooxygenase-2 inhibits UVB-induced apoptosis in mouse skin by activating the prostaglandin E2 receptors, EP2 and EP4.

  2007cited by this paper
• Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice.

  2007cited by this paper
• Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles

  2006cited by this paper
• Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

  2006cited by this paper
• ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles

  2006cited by this paper
• Inhibition of epidermal growth factor‐induced cell transformation and Akt activation by caffeine

  2005cited by this paper
• Cancer in xeroderma pigmentosum and related disorders of DNA repair

  2005cited by this paper
• Caffeine inhibits cell proliferation by G0/G1 phase arrest in JB6 cells.

  2004cited by this paper
• Stimulatory Effect of Topical Application of Caffeine on UVB-Induced Apoptosis in the Epidermis of p53 and Bax Knockout Mice

  2004cited by this paper
• Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling

  2004cited by this paper
• Caffeine Inhibits Checkpoint Responses without Inhibiting the Ataxia-Telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) Protein Kinases*

  2003cited by this paper
• Induction of apoptosis by caffeine is mediated by the p53, Bax, and caspase 3 pathways.

  2003cited by this paper
• Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance.

  2003cited by this paper
• Mitogen-Activated Protein Kinase Activation in UV-Induced Signal Transduction

  2003cited by this paper
• Cyclooxygenase-2 Expression in Murine and Human Nonmelanoma Skin Cancers: Implications for Therapeutic Approaches¶

  2002cited by this paper
• Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis.

  2002cited by this paper
• p53 mutations as a marker of skin cancer risk: comparison of UVA and UVB effects.

  2002cited by this paper
• Direct Effects of Caffeine and Theophylline on p110δ and Other Phosphoinositide 3-Kinases

  2002cited by this paper
• Chk2 Is a Tumor Suppressor That Regulates Apoptosis in both an Ataxia Telangiectasia Mutated (ATM)-Dependent and an ATM-Independent Manner

  2002cited by this paper
• Deficiency in the repair of UV-induced DNA damage in human skin fibroblasts compromised for the ATM gene.

  2002cited by this paper
• Topical applications of caffeine or (−)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice

  2002cited by this paper
• ATR Is Not Required for p53 Activation but Synergizes with p53 in the Replication Checkpoint*

  2002cited by this paper
• p53 mutations as a marker of skin cancer risk: comparison of UVA and UVB effects

  2002cited by this paper
• Genome maintenance mechanisms for preventing cancer

  2001cited by this paper
• Ten years of protein kinase B signalling: a hard Akt to follow.

  2001cited by this paper
• PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?

  2001cited by this paper
• Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability.

  2001cited by this paper
• Persistent p53 mutations in single cells from normal human skin.

  2001cited by this paper
• ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation

  2001cited by this paper
• Roles of Akt and glycogen synthase kinase 3beta in the ultraviolet B induction of cyclooxygenase-2 transcription in human keratinocytes.

  2001cited by this paper
• Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells.

  2000cited by this paper
• Essential role of BETA2/NeuroD1 in development of the vestibular and auditory systems.

  2000cited by this paper
• Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.

  2000cited by this paper
• ATR disruption leads to chromosomal fragmentation and early embryonic lethality.

  2000cited by this paper
• Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation.

  2000cited by this paper
• Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.

  2000cited by this paper
• The DNA damage response: putting checkpoints in perspective

  2000cited by this paper
• The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB.

  1999cited by this paper
• Cellular survival: a play in three Akts.

  1999cited by this paper
• Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition.

  1999cited by this paper
• Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway

  1999cited by this paper
• Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.

  1998cited by this paper
• COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer.

  1998cited by this paper
• Three-dimensional visualization of ultraviolet-induced DNA damage and its repair in human cell nuclei.

  1998cited by this paper
• Clinical and histologic trends of melanoma.

  1998cited by this paper
• Frequent clones of p53-mutated keratinocytes in normal human skin.

  1996cited by this paper
• UV and skin cancer: specific p53 gene mutation in normal skin as a biologically relevant exposure measurement.

  1994cited by this paper
• Induction, repair and accumulation of thymine dimers in the skin of UV-B-irradiated hairless mice.

  1991cited by this paper
• Molecular mechanisms of DNA repair inhibition by caffeine.

  1990cited by this paper
• Cyclobutane-type pyrimidine photodimer formation and induction of ornithine decarboxylase in human skin fibroblasts after UV irradiation.

  1988cited by this paper
• Breast and other cancers in families with ataxia-telangiectasia.

  1987cited by this paper

• Keratinocyte transport of notoginsenoside R1 via ABCG2: A novel mechanism for RNA N6-methyladenosine modification in UVB induced skin sunburn injury.

  2026cites this paper
• Chemopreventive effect of caffeine on arsenite-induced carcinogenesis in lung cancer cells via suppression of p53 and heme oxygenase-1

  2025cites this paper
• Radioprotection or radiosensitization? Unraveling caffeine’s bifurcated effects on radiation-induced damage

  2025influential citation
• Caffeine enhances migration, invasion, and tube formation by upregulating MMP-2 in EVT-like HTR-8/SVneo cells.

  2025cites this paper
• Effects of dose-dependent chronic caffeine consumption in a rat burn wound model: Histopathological and immunohistochemical evaluation

  2024cites this paper
• Nano-Curcumin improves caffeine-induced cerebral alterations in male Wistar rats by modifying oxidative stress, inflammation, and COX-2/NF-κB/Nrf2 signaling

  2024cites this paper
• Coffee consumption, cancer, and healthy aging: epidemiological evidence and underlying mechanisms

  2024cites this paper
• Caffeine Protects Keratinocytes from Trichophyton mentagrophytes Infection and Behaves as an Antidermatophytic Agent

  2024cites this paper
• Caffeine enhances chemosensitivity to irinotecan in the treatment of colorectal cancer.

  2023cites this paper
• Photoprotective Effects of Dendrobium nobile Lindl. Polysaccharides against UVB-Induced Oxidative Stress and Apoptosis in HaCaT Cells

  2023cites this paper
• Photoaging: Reversal of the Oxidative Stress Through Dietary Changes and Plant-Based Products

  2023cites this paper
• Plant Secondary Metabolites against Skin Photodamage: Mexican Plants, a Potential Source of UV-Radiation Protectant Molecules

  2022cites this paper
• Astaxanthin Protects Ultraviolet B-Induced Oxidative Stress and Apoptosis in Human Keratinocytes via Intrinsic Apoptotic Pathway

  2022cites this paper
• Activation of the JNKs/ATM-p53 axis is indispensable for the cytoprotection of dermal fibroblasts exposed to UVB radiation

  2022cites this paper
• Hyperoside and Quercitrin in Houttuynia cordata Extract Attenuate UVB-Induced Human Keratinocyte Cell Damage and Oxidative Stress via Modulation of MAPKs and Akt Signaling Pathway

  2022cites this paper
• A Decade of Research on Coffee as an Anticarcinogenic Beverage

  2021cites this paper
• Traditional Turkish Coffee with Medicinal Effect

  2021cites this paper
• Drug-Target Interaction Prediction Based on Adversarial Bayesian Personalized Ranking

  2021cites this paper
• Cytotoxic and genotoxic effects on human keratinocytes triggered by sphingomyelinase D from Loxosceles venom

  2020cites this paper
• Pleiotropic Effects of Caffeine Leading to Chromosome Instability and Cytotoxicity in Eukaryotic Microorganisms

  2020cites this paper
• Therapeutic use of caffeine in dermatology: A literature review

  2020influential citation
• Predicting keratinocyte carcinoma in patients with actinic keratosis: development and internal validation of a multivariable risk‐prediction model†

  2019cites this paper
• Coffee, tea, caffeine, and risk of nonmelanoma skin cancer in a Chinese population: The Singapore Chinese Health Study.

  2019cites this paper
• Genotoxic effect of caffeine in Yarrowia lipolytica cells deficient in DNA repair mechanisms

  2019cites this paper
• Antioxidants of plant origin in cosmetic products: Physicochemical properties and photoprotective potential

  2018cites this paper
• Tectorigenin, a Flavonoid-Based Compound of Leopard Lily Rhizome, Attenuates UV-B-Induced Apoptosis and Collagen Degradation by Inhibiting Oxidative Stress in Human Keratinocytes

  2018cites this paper
• The role of lipid raft translocation of prohibitin in regulation of Akt and Raf‐protected apoptosis of HaCaT cells upon ultraviolet B irradiation

  2017cites this paper
• Theophylline exhibits anti-cancer activity via suppressing SRSF3 in cervical and breast cancer cell lines

  2017cites this paper
• Réponse des fibroblastes dermiques humains suite à un stress génotoxique induit par un régime d'irradiation chronique aux rayons ultraviolets de type-B

  2017cites this paper
• Coffee, tea and caffeine intake and the risk of non-melanoma skin cancer: a review of the literature and meta-analysis

  2017cites this paper
• The potential role of polyphenols in the modulation of skin cell viability by Aspalathus linearis and Cyclopia spp. herbal tea extracts in vitro

  2016cites this paper
• Inhibiting c-Jun N-terminal kinase partially attenuates caffeine-dependent cell death without alleviating the caffeine-induced reduction in mitochondrial respiration in C2C12 skeletal myotubes.

  2016cites this paper
• The effects of caffeine on wound healing

  2016cites this paper
• Faster DNA Repair of Ultraviolet-Induced Cyclobutane Pyrimidine Dimers and Lower Sensitivity to Apoptosis in Human Corneal Epithelial Cells than in Epidermal Keratinocytes

  2016cites this paper
• Coffee consumption and risk of nonmelanoma skin cancer: a dose–response meta-analysis

  2016cites this paper
• Anti-Inflammatory Effects of Aspalathus linearis and Cyclopia spp. Extracts in a UVB/Keratinocyte (HaCaT) Model Utilising Interleukin-1α Accumulation as Biomarker

  2016cites this paper
• Coffee Consumption and Melanoma: A Systematic Review and Meta-Analysis of Observational Studies

  2016cites this paper
• A genome-wide analysis of gene-caffeine consumption interaction on basal cell carcinoma.

  2016cites this paper
• In Vitro Chemopreventive Properties of Green Tea, Rooibos and Honeybush Extracts in Skin Cells

  2016cites this paper
• Role of Coffea arabica Extract and Related Compounds in Preventing Photoaging and Photodamage of the Skin

  2015cites this paper
• Extreme tolerance and developmental buffering of UV-C induced DNA damage in embryos of the annual killifish Austrofundulus limnaeus.

  2015cites this paper
• Effect of Immunosuppressants Tacrolimus and Mycophenolate Mofetil on the Keratinocyte UVB Response

  2015cites this paper
• Predicting the Risk of a Second Basal Cell Carcinoma.

  2015cites this paper
• Mechanisms of Photoaging and Cutaneous Photocarcinogenesis, and Photoprotective Strategies with Phytochemicals

  2015cites this paper
• Developmental Mechanisms that Support Genome Stability and Embryonic Survival in Stress-tolerant Embryos of the Annual Killifish Austrofundulus limnaeus

  2015influential citation
• Caffeine sensitivity in Drosophila melanogaster

  2015cites this paper
• SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer.

  2014cites this paper
• Tumor and Stem Cell Biology SIRT 6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer

  2014cites this paper
• Phytochemical modulation of the Akt/mTOR pathway and its potential use in cutaneous disease

  2014cites this paper
• Relationship between bladder cancer and total fluid intake: a meta-analysis of epidemiological evidence

  2014cites this paper
• Tea, coffee, and caffeine and early-onset basal cell carcinoma in a case–control study

  2014cites this paper
• Modulation of viability and apoptosis of UVB-exposed human keratinocyte HaCaT cells by aqueous methanol extract of laver (Porphyra yezoensis).

  2014cites this paper
• Protection from UVB Toxicity in Human Keratinocytes by Thailand Native Herbs Extracts

  2014cites this paper
• The role of inflammation in skin cancer.

  2014cites this paper
• Drosophila Mage, a component of Smc5/6 DNA response complex, confers resistance to caffeine and genotoxic stress and plays a role in the cell cycle and cell survival

  2014cites this paper
• In vitro models for investigating keratinocyte responses to ultraviolet B radiation

  2013cites this paper
• Chemopreventive properties of South African herbal teas, rooibos (Aspalathus linearis) and honeybush (Cyclopia spp) : mechanisms against skin carcinogenesis

  2013cites this paper
• USEFULNESS OF ALKALOIDS IN TREATMENT OF CANCER. PART 1: A REVIEW

  2013cites this paper
• Nonmelanoma skin cancer in young women.

  2013cites this paper
• Caffeine suppresses homologous recombination through interference with RAD51-mediated joint molecule formation

  2013influential citation
• The Smc5/Smc6/MAGE Complex Confers Resistance to Caffeine and Genotoxic Stress in Drosophila melanogaster

  2013cites this paper
• Mechanisms of Caffeine-Induced Inhibition of UVB Carcinogenesis

  2013cites this paper
• A dose-response meta-analysis of coffee consumption and bladder cancer.

  2012cites this paper
• Role of AMPK in UVB-induced DNA damage repair and growth control

  2012cites this paper
• Caffeine protects human skin fibroblasts from acute reactive oxygen species-induced necrosis.

  2012cites this paper
• Increased caffeine intake is associated with reduced risk of basal cell carcinoma of the skin.

  2012cites this paper
• Chromatin Structure Following UV-Induced DNA Damage—Repair or Death?

  2011cites this paper
• Chemoprevention of Skin Cancer by Natural Compounds

  2011cites this paper