Activation of the Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Pathway Overcomes Cisplatin Resistance in Ovarian Carcinoma Cells

作者：Nonaka Michiko; Itamochi Hiroaki^*; Kawaguchi Wakae; Kudoh Akiko; Sato Seiya; Uegaki Kazunori; Naniwa Jun; Sato Shinya; Shimada Muneaki; Oishi Tetsuro; Terakawa Naoki; Kigawa Junzo; Harada Tasuku

来源：International Journal of Gynecological Cancer, 2012, 22(6): 922-929.

DOI：10.1097/IGC.0b013e31824f0b13

• Cisplatin
• Resistance
• MEK/ERK
• Ovarian carcinoma
• Molecular targeted therapy

Objective: This study was aimed to elucidate the roles of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3%26apos;-kinase (PI3K)/Akt pathways in regulating cytotoxicity induced by cisplatin (CDDP) in ovarian carcinoma cells. %26lt;br%26gt;Methods: We treated 7 ovarian cancer cell lines with CDDP alone or with CDDP and either a PI3K inhibitor (LY294002), a MEK inhibitor (PD98059), or a MEK/ERK activator (phorbol 12-myristate 13-acetate [PMA]) and assessed cell viability, expression of MEK/ERK and PI3K/Akt, cell cycle distribution, and apoptosis. We also investigated the effect of combination treatment on survival in a xenograft model. %26lt;br%26gt;Results: The cell lines showed half-maximal inhibitory concentrations (IC50) of CDDP from 2.4 to 26.9 mu mol/L. KFr, a CDDP-resistant cell line developed from KF cells, showed an IC50 of CDDP of 9.6 mu mol/L. Five of the cell lines with IC50 values of 9.6 mu mol/L or greater were defined as CDDP-resistant. Cisplatin and LY294002 had an additive effect on inhibiting cell growth, and CDDP and PD98059 had and antagonistic effect on cell growth in all cell lines. In CDDP-resistant cells, CDDP and PMA dramatically suppressed the cell growth, up-regulated the expression of phosphorylated ERK and cleaved caspase-9, down-regulated the expression of checkpoint kinases, and increased the proportion of cells in the synthesis-phase fraction and apoptotic cells. The treatment of nude mice with CDDP and PMA prolonged survival in an ovarian cancer xenograft model. %26lt;br%26gt;Conclusions: The present study indicates that further study is warranted to determine the effectiveness of combination treatment with CDDP and PMA for platinum-resistant ovarian carcinoma.

• 出版日期2012-7