Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line.

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.