title: Involvement of Akt isoforms in chemoresistance of endometrial carcinoma cells.
abstract: OBJECTIVE
  In tumors, upstream regulation of Akt is affected by oncogenic events which lead to its constitutive activation and promote cell survival. Since studies have demonstrated that the three Akt isoforms exhibit different physiological functions, Akt isoforms may contribute differently in chemoresistance. The objective of the study was to determine the role of each Akt isoforms in chemoresistance.
  
  
  METHODS
  We stably transfected the chemoresistant KLE endometrial carcinoma cells with specific shRNAs for Akt1, Akt2 or Akt3. Alternatively, we stably transfected the chemosensitive Hec-1-A endometrial carcinoma cells, in which no Akt activity is detected, with constitutively active Akt expression vectors for each isoform.
  
  
  RESULTS
  We demonstrated that Akt1 and Akt2 downregulation by RNAi highly sensitizes KLE cells to cisplatin by inducing the activation of pro-apoptotic factors such as the cleavage of caspases-3, -6, -9 and PARP; downregulation of all Akt isoforms leads to increased sensitivity to doxorubicin while only Akt1-2 downregulation increases taxol sensitivity. Proliferation of Akt1, and mostly Akt2 deficient cells was affected by cisplatin treatment. Constitutive Akt1 or Akt2 expression led to an increased resistance to apoptosis. Akt isoforms have been shown to influence migration in other cancer cells. We showed that Akt2 blocks cell motility, while Akt1-3 had less effect on our endometrial cancer cell models.
  
  
  CONCLUSIONS
  Our findings highlight the contribution of Akt1 and Akt2 in the molecular mechanisms that govern chemoresistance of endometrial carcinomas. Furthermore, Akt isoform-specific transfectants will provide a strong model to determine the involvement of each Akt isoform in tumor progression and metastasis.
authors.affiliation: Canada Research Chair in Molecular Gyneco-Oncology, Research Group in Molecular Oncology and Endocrinology, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada G9A 5H7.
authors.forename: Julie
authors.initials: J
authors.lastname: Girouard
authors.forename: Marie-Judith
authors.initials: MJ
authors.lastname: Lafleur
authors.forename: Sophie
authors.initials: S
authors.lastname: Parent
authors.forename: Valérie
authors.initials: V
authors.lastname: Leblanc
authors.forename: Eric
authors.initials: E
authors.lastname: Asselin
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D007527:Isoenzymes; D034741:RNA, Small Interfering; D004317:Doxorubicin; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin