title: Multiple effects of digoxin on subsets of cancer-associated genes through the alternative splicing pathway.
abstract: The signaling characteristics of Na(+)/K(+)-ATPase are distinct from its ion pumping activity. Cardiac glycosides modulate the Na(+)/K(+)-ATPase protein complex upon binding, activate downstream signaling pathways and increase [Ca(2+)]i. Recent studies demonstrate that the depletion of p53 and hypoxia-induced factor 1α proteins is caused by cardiac glycosides. However, the detailed mechanisms governing this process are not well known. In this study, we showed that the depletion of p53 proteins by digoxin involved not only inhibition of protein synthesis but also inhibition at the post-transcriptional level. Post-transcriptional regulation occurs via down-regulation of SRSF3, the primary splicing factor responsible for the switch from p53α to the p53β isoform. Digoxin also modulated G2/M arrest, DNA damage and apoptosis through the p53-dependent pathway in HeLa cells. In addition, digoxin was involved in epithelial-mesenchymal-transition progression via E-cadherin reduction and snail induction. Digoxin had similar effects to caffeine, another SRSF3-reduced agent, on the cell cycle profile and DNA damage of cells. Interestingly, combined digoxin and caffeine treatment blocked cell cycle progression and conferred resistance to cell death via snail induction. These findings demonstrate that down-regulation of splicing factor, such as SRSF3, to alter cell cycle progression, cell death and invasion is a potential target for the drug repositioning of cardiac glycosides.
authors.affiliation: 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.forename: Guan-Yu
authors.initials: GY
authors.lastname: Lu
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei City 114, Taiwan, ROC.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei City 114, Taiwan, ROC. Electronic address: shihming@ndmctsgh.edu.tw.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei City 114, Taiwan, ROC.
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chang
authors.affiliation: 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.forename: Wei-Shiang
authors.initials: WS
authors.lastname: Lin
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D004077:Digoxin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction / Q000235:genetics*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D002316:Cardiotonic Agents; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000068103:Serine-Arginine Splicing Factors; D004077:Digoxin
keywords: Alternative splicing; Cardiac glycosides; Digoxin; Drug repositioning; SRSF3