title: The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway.
abstract: BACKGROUND
  Cisplatin (CDDP) is one of the most important chemotherapeutic agents in the treatment of advanced gastric cancer, but its efficacy is limited by CDDP resistance. Because the transcription factor FOXO1 is related to chemoresistance in various cancer cells, we investigated the function of FOXO1 in CDDP resistance in human gastric cancer cells.
  
  
  METHODS
  Human gastric cancer cell lines MKN45 and SNU-601 were used. FOXO1 activation was modulated by transfection of FOXO1 AAA mutant gene or FOXO1 shRNA. The effects of FOXO1 on cell growth and CDDP cytotoxicity were assessed by crystal violet assay. Protein expressions of FOXO1, p110α, pAkt, and Akt were analyzed by Western blotting, and FOXO1 mRNA expression was evaluated by semiquantitative reverse transcription-polymerase chain reaction. FOXO1 activity was determined by luciferase reporter assay, and cell apoptosis was assessed by DAPI staining and Western blotting for PARP cleavage.
  
  
  RESULTS
  Cisplatin treatment induced FOXO1 expression and activation in both gastric cancer cell lines. FOXO1 overexpression increased the CDDP resistance without changes in cell growth, whereas FOXO1 silencing enhanced CDDP cytotoxicity along with apoptotic characteristics. Both constitutive and CDDP-induced FOXO1 activations were accompanied by an increase in p110α and pAkt expression. Furthermore, Akt inhibition by LY294002 treatment restored the CDDP cytotoxicity that was suppressed by FOXO1 overexpression.
  
  
  CONCLUSIONS
  FOXO1 inhibits CDDP-induced apoptosis in gastric cancer cells via activating PI3K/Akt pathway. Thus, FOXO1 may be an useful pharmacological indicator to predict CDDP efficacy in gastric cancer treatment.
authors.affiliation: Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jinju
authors.initials: J
authors.lastname: Park
authors.forename: Young San
authors.initials: YS
authors.lastname: Ko
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Yoon
authors.forename: Min A
authors.initials: MA
authors.lastname: Kim
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Youngsun
authors.initials: Y
authors.lastname: Choi
authors.forename: Ji Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Younghee
authors.initials: Y
authors.lastname: Cheon
authors.forename: Byung Lan
authors.initials: BL
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin