title: YM155 induces apoptosis through downregulation of specificity protein 1 and myeloid cell leukemia-1 in human oral cancer cell lines.
abstract: BACKGROUND
  YM155 is a small-molecule pro-apoptotic agent which has shown to inhibit survivin expression and induce apoptosis in various cancer cells. In this study, we investigated the function and molecular mechanism of YM155 in human oral cancer cells.
  
  
  METHODS
  The apoptotic effects and related signaling pathways of YM155 were evaluated using trypan blue exclusion assay, 4'-6-diamidino-2-phenylindole staining, Western blotting, RT-PCR, and siRNA.
  
  
  RESULTS
  YM155 inhibited the growth and caused caspase-dependent apoptosis in MC3 and HN22 cells. YM155 significantly suppressed the level of survivin protein expression through proteasome-dependent protein degradation to confirm its survivin-inhibiting function. YM155 reduced myeloid cell leukemia-1 (Mcl-1) protein, but it did not alter Mcl-1 mRNA. It was associated with the facilitation of lysosome-dependent protein degradation. The modifications of Mcl-1 and survivin by YM155 were caspase-independent manner. Treatment of MC-3 and HN22 cells with YM155 inhibited specificity protein 1 (Sp1) and the knockdown of Sp1 by siRNA demonstrated that Mcl-1 was regulated by Sp1 protein.
  
  
  CONCLUSIONS
  We demonstrated the novel mechanism that YM155 causes apoptosis of human oral cancer cell lines through downregulation of Sp1 and Mcl-1. Therefore, it may be a potential anticancer drug candidate for the treatment of oral cancer.
authors.affiliation: Department of Oral Pathology, School of Dentistry, Institute of Biodegradable Material, Institute of Oral Bioscience, Chonbuk National University, Jeonju, Korea.
authors.forename: Khadka
authors.initials: K
authors.lastname: Sachita
authors.affiliation: Department of Oral Pathology, School of Dentistry, Institute of Biodegradable Material, Institute of Oral Bioscience, Chonbuk National University, Jeonju, Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Yu
authors.affiliation: Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: Department of Health and Functional Food, College of Medical Science, Jeonju University, Jeonju, Korea.
authors.forename: Jeong-Sang
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Oral Pathology, School of Dentistry, Institute of Biodegradable Material, Institute of Oral Bioscience, Chonbuk National University, Jeonju, Korea.
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Cho
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009285:Naphthoquinones; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D000077022:Survivin; D053148:Caspase 3; C523798:sepantronium
keywords: YM155; apoptosis; myeloid cell leukemia-1; oral cancer; specificity protein 1