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Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

The Pharmacogenomics Journal volume 10, pages 94–104 (2010)Cite this article

Abstract

Drug resistance in cancer cells involves complex molecular mechanisms and ovarian carcinoma cells become resistant to chlorambucil (Cbl) after continuous treatment. This drug- and ionizing radiation-resistant cells have lower level of endogenous ROS (reactive oxygen species) compared with sensitive cells. Elevation of the cellular ROS level by exogenous ROS generation increases the sensitivity of Cbl to resistant cells. In contrast, antioxidants prevent the sensitization of resistant cells to Cbl by H2O2, COS (chronic oxidative stress) or NOO−. The molecular mechanism of drug sensitivity with COS has been investigated by microarray gene expressions followed by gene network analysis and it reveals that a cdc42/rac1 guanine exchange factor, ARHGEF6, with p53 and DNA-Pkc (PRKDC) is central to induce apoptosis in Cblcos (Cbl with COS) cells. mRNA and protein levels of major gene network pathway differ significantly in Cblcos cells than in Cbl-treated cells. Moreover, DNA-PKc physically interacts with ARHGEF6 and p53 mostly in the nucleus of Cbl-treated cells, whereas in Cblcos-treated cells, its interactions are mostly in the cytoplasm. These results suggest that low doses of Cbl and very low doses of COS together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cblcos cells.

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Abbreviations

ERCC-4 :

excision repair cross-complementing rodent repair deficiency gene, complementation group 4

BCNU:

bis-chloronitrosourea, a generic anticancer drug named Carmustine

QPCR:

quantitative PCR

GSH:

glutathione

s.e.m.:

standard error of the mean

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Acknowledgements

I thank Dr I Boldogh for gifting A2780 and A2780/100 cells; Dr G Das for standardizing COS treatment; Dr M Sinha in the bioinformatics division for analyzing microarray data; Silicon Genetics and Spotfire Inc. for using GeneSpring and Spotfire software, respectively. I thank anonymous reviewers for critical comments for improving the paper.

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  1. A&I, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    A K Maiti

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Correspondence to A K Maiti.

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Maiti, A. Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells. Pharmacogenomics J 10, 94–104 (2010). https://doi.org/10.1038/tpj.2009.49

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