title: A novel antioxidant 3-O-Caffeoyl-1-methylquinic acid enhances ultraviolet A-mediated apoptosis in immortalized HaCaT keratinocytes via Sp1-dependent transcriptional activation of p21(WAF1/Cip1).
abstract: It has become clear that ultraviolet A (UVA) radiation from the solar spectrum is a major environmental challenge to the skin. This necessitates developing novel mechanism-based agents capable of ameliorating UVA-induced effects in the skin. We recently described a novel antioxidant, 3-O-Caffeoyl-1-methylquinic acid (MCGA3) from leaves of bamboo. Here, we investigated the photochemopreventive effects of MCGA3 against UVA-mediated apoptosis in immortalized HaCaT keratinocytes. Pretreatment of MCGA3 rendered cells more sensitive to subsequent UVA irradiation-induced apoptosis as well as completely reversed UVA-induced sustained phosphorylation of extracellular signal-regulated kinase 1/2 and protein kinase Calpha, downregulation of p21, and reactive oxygen species generation. Interestingly, MCGA3 itself effectively induced p21 protein and mRNA levels. Silencing of p21 by RNA interference revealed a pivotal role of p21 in generating G(1)-S arrest and in enhancing UVA-mediated apoptosis. Transcriptional activation of p21 by MCGA3 was mediated through the proximal region of multiple Sp1 sites regardless of p53-binding site in p21 promoter, and this effect was augmented by desferroioxamine, an iron chelating agent. Additional studies suggested that iron chelation-driven hypoxia by MCGA3 may function in activation of p21. MCGA3 could be a useful agent to prevent photocarcinogenesis via apoptotic elimination of p53 mutant and DNA-repair defective cells caused by UVA radiation.
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: M-H
authors.initials: MH
authors.lastname: Kweon
authors.forename: F
authors.initials: F
authors.lastname: Afaq
authors.forename: K M R
authors.initials: KM
authors.lastname: Bhat
authors.forename: V
authors.initials: V
authors.lastname: Setaluri
authors.forename: H
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000378:metabolism; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: C490257:3-O-caffeoyl-1-methylquinic acid; D000975:Antioxidants; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D011801:Quinic Acid