title: Caffeine decreases phospho-Chk1 (Ser317) and increases mitotic cells with cyclin B1 and caspase 3 in tumors from UVB-treated mice.
abstract: Oral administration of caffeine to mice inhibits UVB-induced carcinogenesis, and these results are paralleled by epidemiology studies indicating that caffeinated coffee and tea intake (but not decaffeinated beverage intake) is associated with decreased incidence of nonmelanoma skin cancer. Topical applications of caffeine to the skin of SKH-1 mice that had previously been treated with UVB inhibited subsequent skin tumor development and stimulated apoptosis in tumors but not in nontumor areas of the epidermis. This study sought to determine the basis of these differential effects on tumor versus nontumor sites that can be induced by caffeine, long after all UVB treatment has ceased. The activation status of the ATR/Chk1 pathway in UVB-induced tumors and uninvolved skin was determined by quantitating phospho-Chk1 (Ser317) and induction of lethal mitosis in vivo in the presence and absence of topical caffeine treatment. In the absence of caffeine, we found that UVB-induced tumors often had islands of phospho-Chk1 (Ser317) staining cells that were not present in nontumor areas of the epidermis. Treatment of mice with topical caffeine significantly diminished phospho-Chk1 (Ser317) staining and increased the number of mitotic cells that expressed cyclin B1 and caspase 3 in tumors, consistent with caffeine-induced lethal mitosis selectively in tumors. We hypothesize that compared with adjacent uninvolved skin, UVB-induced skin tumors have elevated activation of, and dependence on, the ATR/Chk1 pathway long after UVB exposure has ceased and that caffeine can induce apoptosis selectively in tumors by inhibiting this pathway and promoting lethal mitosis.
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
authors.forename: Yao-Ping
authors.initials: YP
authors.lastname: Lu
authors.forename: You-Rong
authors.initials: YR
authors.lastname: Lou
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Peng
authors.forename: Paul
authors.initials: P
authors.lastname: Nghiem
authors.forename: Allan H
authors.initials: AH
authors.lastname: Conney
mesh_terms: D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002110:Caffeine / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D000071877:Checkpoint Kinase 1; D056744:Cyclin B1 / Q000378:metabolism*; D005260:Female; D015151:Immunoblotting; D051379:Mice; D008812:Mice, Hairless; D008938:Mitosis / Q000187:drug effects* / Q000528:radiation effects; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011494:Protein Kinases / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D014466:Ultraviolet Rays
chemical_list: D000697:Central Nervous System Stimulants; D056744:Cyclin B1; D002110:Caffeine; D012694:Serine; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D053148:Caspase 3