title: Akt activity in endometrial cancer cells: regulation of cell survival through cIAP-1.
abstract: In a number of different cancer including endometrial cancers, tumor suppressor phosphatase tensin homologue (PTEN, a lipid phosphatase) is frequently mutated. PTEN dephosphorylates PI 3-K product, phosphatidylinositol 3,4,5-triphosphate (PIP3), into inactive PIP2 which blocks Akt activation/phosphorylation. In the present study, we have used an endometrial cancer cell line known to possess wild-type PTEN (HEC-1-A) and two mutated inactive PTEN protein cell lines (RL-95-2 and Ishikawa) to investigate importance of PI 3-K/PTEN/Akt survival pathway in endometrial cancers. As hypothesised, results showed high levels of Akt1/2 mRNAs and protein phosphorylation in the two mutated PTEN human endometrial cancer cells. To test the possible involvement of Akt in the regulation of survival factors, Bcl-2, XIAP, cIAP-1 and cIAP-2 expression were measured. cIAP-1 protein expression was high in cells expressing phospho-Akt. XIAP and cIAP-2 protein expression was not influenced by the presence of active Akt. Akt phosphorylation decreased and apoptosis was strongly increased in mutated PTEN human endometrial cancer cells in the presence of PI 3-K inhibitor (Wortmannin) which was accompanied by a down-regulation of cIAP-1 protein. Wortmannin had no effect on wild-type PTEN HEC-1-A cell line. Although, Bcl-2 expression was strongly expressed in mutated-PTEN cells, expression remained stable in the presence of Wortmannin suggesting that Bcl-2 is not regulated by Akt. Overexpression of Akt using a constitutively active Akt expression vector resulted in an up-regulation of cIAP-1 expression. These results suggest a pivotal role of Akt in the regulation of endometrial cancer cell survival through the up-regulation of a specific inhibitor of apoptosis protein.
authors.affiliation: Department of Chemistry and Biology, Medical Biology Section, University of Quebec at Trois-Rivieres, C.P. 500, Trois-Rivieres, Quebec G9A 5H7, Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Gagnon
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: St-Germain
authors.forename: Sophie
authors.initials: S
authors.lastname: Parent
authors.forename: Eric
authors.initials: E
authors.lastname: Asselin
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008954:Models, Biological; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases; D000077191:Wortmannin; C494833:BIRC2 protein, human; C494918:AKT1 protein, human