Abstract
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 p110α 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.
Original language | English |
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Pages (from-to) | 26-34 |
Number of pages | 9 |
Journal | Gynecologic Oncology |
Volume | 97 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2005 Apr |
Bibliographical note
Funding Information:This work was supported in part by a grant F00061 from Korea Research Foundation and in part by interin fund of Korea Institute of Science and Technology.
Keywords
- Apoptosis
- Bax translocalization
- Cisplatin resistance
- Cytochrome c
- OVCAR-3 cells
- PI3K/Akt
- PIK3CA
- PTEN
ASJC Scopus subject areas
- Oncology
- Obstetrics and Gynaecology