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: Veronique Gagnon, Marie-Eve St-Germain, Sophie Parent, Eric Asselin
• Journal: International journal of oncology (Int J Oncol) Vol. 23 Issue 3 Pg. 803-10 (Sep 2003) ISSN: 1019-6439 [Print] Greece
• PMID: 12888921 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androstadienes
• Coloring Agents
• Enzyme Inhibitors
• Inhibitor of Apoptosis Proteins
• Proteins
• Proto-Oncogene Proteins
• RNA, Messenger
• BIRC2 protein, human
• Ubiquitin-Protein Ligases
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Apoptosis
• Blotting, Western
• Cell Line, Tumor
• Cell Survival
• Coloring Agents (pharmacology)
• Endometrial Neoplasms (metabolism)
• Enzyme Inhibitors (pharmacology)
• Female
• HeLa Cells
• Humans
• Inhibitor of Apoptosis Proteins
• Models, Biological
• Mutation
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases
• Proteins (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Transfection
• Ubiquitin-Protein Ligases
• Up-Regulation
• Wortmannin