title: Caffeine induces tumor cytotoxicity via the regulation of alternative splicing in subsets of cancer-associated genes.
abstract: Caffeine causes a diverse range of pharmacological effects that are time- and concentration-dependent and reversible. The detailed mechanisms of caffeine in tumor suppression via tumor suppressor protein p53 remain unclear. The isoforms of p53 are physiological proteins that are expressed in normal cells and generated via alternative promoters, splicing sites and/or translational initiation sites. In this study, we investigated how caffeine modulated cell cycle arrest and apoptosis via the expression of various alternatively spliced p53 isoforms. Caffeine reduced p53α expression and induced the expression of p53β, which contains an alternatively spliced p53 C-terminus. In HeLa cells, the expression levels of many serine/arginine-rich splicing factors, including serine/arginine-rich splicing factors 2 and 3, were altered by caffeine. Serine/arginine-rich splicing factor 3 was a promising candidate for the serine/arginine-rich splicing factors responsible for the alternative splicing of p53 in response to caffeine treatment. In addition to p53-dependent functions, multiple target genes of serine/arginine-rich splicing factor 3 suggest that caffeine can regulate epithelial-mesenchymal-transition and hypoxic conditions to inhibit the survival of tumor cells. In summary, our data provide a new pathway of caffeine-modulated tumor suppression via the alternative splicing of the target genes of serine/arginine-rich splicing factor 3.
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City 114, Taiwan, ROC; Department of Pharmacy, Shalu Division, Kuang Tien General Hospital, Taichung 433, Taiwan, ROC.
authors: Guan-Yu
authors: GY
authors: Lu
authors: Department of Biochemistry, National Defense Medical Center, Taipei City 114, Taiwan, ROC.
authors: Shih-Ming
authors: SM
authors: Huang
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City 114, Taiwan, ROC; Department of Biochemistry, National Defense Medical Center, Taipei City 114, Taiwan, ROC.
authors: Shu-Ting
authors: ST
authors: Liu
authors: Department of Biochemistry, National Defense Medical Center, Taipei City 114, Taiwan, ROC.
authors: Pei-Yao
authors: PY
authors: Liu
authors: Department of Biochemistry, National Defense Medical Center, Taipei City 114, Taiwan, ROC.
authors: Wei-Yuan
authors: WY
authors: Chou
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City 114, Taiwan, ROC; Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan, ROC. Electronic address: wslin545@ms27.hinet.net.
authors: Wei-Shiang
authors: WS
authors: Lin
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000077150:Oxaliplatin; D020033:Protein Isoforms; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000068103:Serine-Arginine Splicing Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D009944:Organoplatinum Compounds; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D000068103:Serine-Arginine Splicing Factors; D002110:Caffeine
keywords: ACTN; Alternative splicing; COX-2; Caffeine; EGFR; EMT; FASN; Glut1; HIF-1α; KLF6; Krüppel-like factor 6; SR; SREBP1c; SRSF3; Splicing factor; VEGF; alpha actinin; cyclooxygenase-2; epidermal growth factor receptor; epithelial-mesenchymal-transition; fatty acid synthase; glucose transporter 1; hypoxia inducible factor 1α; l-OHP; l-oxaliplatin; p53; serine/arginine-rich; sterol regulatory element-binding protein 1c; vascular endothelial growth factor