Skip Navigation LinksHome > July 2012 - Volume 22 - Issue 6 > Activation of the Mitogen-Activated Protein Kinase Kinase/Ex...
International Journal of Gynecological Cancer:
doi: 10.1097/IGC.0b013e31824f0b13
Basic Science

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

Nonaka, Michiko MD; Itamochi, Hiroaki MD, PhD; Kawaguchi, Wakae MD, PhD; Kudoh, Akiko MD; Sato, Seiya MD, PhD; Uegaki, Kazunori MD, PhD; Naniwa, Jun MD, PhD; Sato, Shinya MD, PhD; Shimada, Muneaki MD, PhD; Oishi, Tetsuro MD, PhD; Terakawa, Naoki MD, PhD; Kigawa, Junzo MD, PhD; Harada, Tasuku MD, PhD

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Abstract

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′-kinase (PI3K)/Akt pathways in regulating cytotoxicity induced by cisplatin (CDDP) in ovarian carcinoma cells.

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.

Results: The cell lines showed half-maximal inhibitory concentrations (IC50) of CDDP from 2.4 to 26.9 μmol/L. KFr, a CDDP-resistant cell line developed from KF cells, showed an IC50 of CDDP of 9.6 μmol/L. Five of the cell lines with IC50 values of 9.6 μmol/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.

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.

Copyright © 2012 by IGCS and ESGO

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