title: Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line.
abstract: OBJECTIVE
  The aim of this study was to understand the role of PIK3CA and PTEN on the resistance of human ovarian cancer cells to cisplatin-induced apoptosis.
  
  
  METHODS
  Human ovarian cancer cell OVCAR-3 and cisplatin-resistant subclone OVCAR-3/CDDP cells were used for these studies. The expressions of apoptosis regulating proteins and PI3K/Akt signaling proteins were systematically examined.
  
  
  RESULTS
  OVCAR-3/CDDP cells were 4.8-fold more resistant to cisplatin compared to OVCAR-3 cells following 72 h exposure to this drug. This resistance was paralleled with reduced susceptibility to cisplatin-induced apoptosis. Apoptotic proteins were differentially expressed in OVCAR-3/CDDP cells, resulting in the inhibition of Bax translocalization. Cisplatin inhibited Akt phosphorylation and activation in OVCAR-3 cells but not in OVCAR-3/CDDP cells. The specific PI3K inhibitors LY294002 and wortmannin sensitized OVCAR-3/CDDP cells to cisplatin-induced apoptosis and decreased cell viability. A low level of PTEN expression was strongly associated with amplified PIK3CA and PI3K/Akt activities in OVCAR-3/CDDP cells. Small interfering RNA knockdown of PTEN and the expression of active p110alpha resulted in a blockade of apoptosis by cisplatin in OVCAR-3 cells.
  
  
  CONCLUSIONS
  These results collectively indicate that the development of resistance in OVCAR-3 cells was derived by increased PIK3CA transcription and reduction of PTEN expression. These alterations conferred cisplatin resistance to cisplatin through the activation of PI3K/Akt and the inhibition of Bax translocation.
authors.affiliation: Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Sooyong
authors.initials: S
authors.lastname: Lee
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
authors.forename: Changbae
authors.initials: C
authors.lastname: Jin
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D014408:Biomarkers, Tumor; D002945:Cisplatin; D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; C494929:PTEN protein, human