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Epithelial–mesenchymal status renders differential responses to cisplatin in ovarian cancer

Abstract

Chemoresistance to platinums, such as cisplatin, is of critical concern in the treatment of ovarian cancer. Recent evidence has linked epithelial–mesenchymal transition (EMT) as a contributing mechanism. The current study explored the connection between cellular responses to cisplatin and EMT in ovarian cancer. Expression microarrays were utilized to estimate the EMT status as a binary phenotype, and the transcriptional responses of 46 ovarian cancer cell lines to cisplatin were measured at dosages equivalent to 50% growth inhibition. Phenotypic responses to cisplatin were quantified with respect to cell number, proliferation rate and apoptosis, and then compared with the epithelial or mesenchymal status. Ovarian cancer cell lines with an epithelial status exhibited higher resistance to cisplatin treatment in the MTS assay than those with a mesenchymal status. Pathway analyses revealed the induction of G1/S- and S-phase genes (P=0.001) and the activation of multiple NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) downstream genes (P=0.0016) by cisplatin selectively in epithelial-like cell lines. BrdU incorporation and Caspase-3/7 release assays confirmed impaired apoptosis in epithelial-like ovarian cancer cells. In clinical samples, we observed resistance to single platinum treatment and the selective activation of the NF-κB pathway by platinum in ovarian cancers with an epithelial status. Overall, our results suggest that, in epithelial-like ovarian cancer cells, NF-κB activation by cisplatin may lead to defective apoptosis, preferential proliferation arrest and a consequential decreased sensitivity to cisplatin.

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Acknowledgements

We thank Drs K Yamaguchi, N Matsumura and S Murphy for kindly providing us with a panel of ovarian cancer cell lines. We thank Dr R Jackson for her careful editing of the English language. This work was supported in part through a grant from the Cancer Science Institute of Singapore, the Institute of Molecular and Cell Biology at A*STAR, Singapore, the Vehicle Racing Commemorative Foundation in Japan and the Princess Takamatsu Cancer Research Fund.

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Miow, Q., Tan, T., Ye, J. et al. Epithelial–mesenchymal status renders differential responses to cisplatin in ovarian cancer. Oncogene 34, 1899–1907 (2015). https://doi.org/10.1038/onc.2014.136

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