Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro

Hahne,J.  C.; Honig,A.; Meyer,S. R.; Gambaryan,S.; Walter,U.; Wischhusen,J.; Häussler,S. F.M.; Segerer,S. E.; Fujita,N.; Dietl,J.; Engel,J. B.

doi:10.3892/or.2012.2041

Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro

Authors:
- J. C. Hahne
- A. Honig
- S. R. Meyer
- S. Gambaryan
- U. Walter
- J. Wischhusen
- S. F.M. Häussler
- S. E. Segerer
- N. Fujita
- J. Dietl
- J. B. Engel
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Affiliations: Department of Gynecology, University of Würzburg, D-97080 Würzburg, Germany, Institute for Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, D-97080 Würzburg, Germany, The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan, Department of Gynecology, University of Regensburg, D-93055 Regensburg, Germany
Published online on: September 18, 2012 https://doi.org/10.3892/or.2012.2041
Pages: 2023-2028

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Abstract

Platinum resistance is the most crucial problem for treatment of ovarian cancer. Increasing evidence points towards AKT overexpression as a mechanistic reason for this clinical condition. The present study evaluates the effect of overexpression and downregulation of AKT on the sensitivity to cisplatin in a platinum-resistant human ovarian cancer cell line and the corresponding platinum-sensitive parental cell line. A2780 and A2780cis ovarian cancer cell lines were stably transfected with an AKT-sense and AKT-antisense plasmid. Successful transfection was evaluated by western blot analysis. Cytotoxic effects of cisplatin were evaluated by metabolic (MTT) and clonogenicity assays as well as by FACS analysis. AKT overexpression (confirmed by western blotting) converted platinum-sensitive A2780 into platinum-resistant cells as shown by MTT assay. Importantly, platinum resistance of A2780cis cells could be reversed by downregulation of AKT, as demonstrated by MTT and clonogenicity assays and FACS analysis. Our data provide strong evidence that cisplatin resistance in ovarian cancer is mediated by AKT overexpression and can be overcome by AKT downregulation, thus, providing a rationale for clinical phase II/III studies combining AKT inhibitors with cisplatin.

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