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

• Published in: Gynecologic oncology 2005-04, Vol.97 (1), p.26-34
• Main Authors: Lee, Sooyong, Choi, Eui-Ju, Jin, Changbae, Kim, Dong-Hyun
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Bax translocalization; bcl-2-Associated X Protein; bcl-X Protein; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Cell Line, Tumor; Cisplatin - pharmacology; Cisplatin resistance; Class I Phosphatidylinositol 3-Kinases; Cytochrome c; Drug Resistance, Neoplasm; Enzyme Activation; Female; Gene Amplification; Humans; Intracellular Membranes - metabolism; Mitochondria - metabolism; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; OVCAR-3 cells; Oxidation-Reduction; Phosphatidylinositol 3-Kinases - biosynthesis; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphoric Monoester Hydrolases - metabolism; PI3K/Akt; PIK3CA; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2 - metabolism; PTEN; PTEN Phosphohydrolase; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Transcription, Genetic - drug effects; Tumor Suppressor Proteins - metabolism
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2004.11.051

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. 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. 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. 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.