PARENT SESSION
BIOLOGY OF THE FEMALE REPRODUCTIVE TRACT
Harborside C
7:30 AM-10:00 AM

(547) REGULATION OF THE PI 3-K/Akt SURVIVAL PATHWAY THROUGH PTEN IN HUMAN ENDOMETRIAL CANCER CELLS .

Gagnon, Veronique¹, St-Germain, Marie-Eve¹, Parent, Sophie¹, Asselin, Eric¹, ¹ Departement de Chimie-Biologie, Trois-Rivieres, CA

ABSTRACT- Endometrial cancer is the leading type of female genital cancer in the Western world and is the fourth most common cancer in women. It is known that cancer cells differentiate from normal cells because they have undergone several mutations. In a number of different cancer, 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. Akt phosphorylation leads to activation of different survival pathways and disable apoptotic processes such as caspases cascade activation and cytochrome C release from mitochondria. However, in the absence of active PTEN, PI 3-K induces Akt phosphorylation and this survival pathway. In the present study, we have developped a new model to investigate the role of PTEN in the regulation of PI 3-K/Akt survival pathway. Four different endometrial cancer (HEC) cell lines know to possess wild-type PTEN (HEC-1-A and KLE) and mutated inactive PTEN protein (RL-95-2 and Ishikawa) were used for these studies. Results showed high levels of Akt phosphorylation in mutated PTEN HEC cells. Surprisignly, the presence of Akt phosphorylation was observed in KLE wild-type PTEN cells and analysis of PTEN protein expression in this cell line revealed that levels were high compared to the other HEC cells. Further analyses revealed that the level of X-linked inhibitor of apoptosis protein (XIAP, a well known caspase inhibitor) was high in KLE cell line when compare to the other HEC cells. Akt phosphorylation decreased and apoptosis was strongly increased in mutated PTEN HEC cells in the presence of PI 3-K inhibitors (Wortmannin and LY294002). However, KLE cells remained resistant to PI 3-K inhibitors. These results demonstrate for the first time that XIAP regulates Akt activity through a distinct pathway other than PI 3-K. Furthermore, the model proposed will help to determine the importance of PTEN in the control of cell survival through the PI 3-K/Akt pathway in HEC cells.

KEY WORDS: Endometrium, Cancer, Apoptosis, PI 3-K / Akt