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Mitochondrial DNA determines the cellular response to cancer therapeutic agents

Oncogene volume 18, pages 6641–6646 (1999)Cite this article

Abstract

Mutations in the mitochondrial genome leading to mitochondrial dysfunction have been reported in a variety of cancers. However, the potential implication of these findings in the cellular response to cancer therapeutic agents is unclear. To examine the importance of mitochondrial DNA (mitDNA) encoded functions in cancer therapeutic response, we determined the clonogenic survival of HSL2 (Rho+, HeLa subline), and its derivative cell line lacking mitDNA (Rho0) after exposure to different anticancer agents. We found that isogenic Rho0 cells lacking mitDNA were extremely resistant to adriamycin and photodynamic therapy (PDT) induced cell death, whereas the Rho+ cell line was sensitive. However, there was no measurable difference in the responses of these cell lines to either alkylating agent or γ-radiation. We show that the development of resistance to adriamycin was not due to changes in apoptotic cell death, cell cycle response or to the uptake of adriamycin in isogenic Rho0 cells. We also demonstrate that exposure of HeLa cells to adriamycin leads to mutations in mitDNA. These studies provide direct evidence that mitDNA plays an important role in cellular sensitivity to cancer therapeutic agents.

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Acknowledgements

This work was supported by grants from Alexander and Margaret Stewart Trust, CA/ES 66204, ES 09714-01 and American Heart Association 9930223N to KK Singh and the Plotkin – Katz Foundation to KF Keshav. We thank Dr Rejean Morais for the kind gift of HSL2 and its mitDNA-less derivative cell lines. We also thank Dr Michael King for the mitDNA probe used in this study.

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Authors and Affiliations

  1. Johns Hopkins Oncology Center, 600 North Wolfe Street, Room 2-121, Baltimore, 21287, Maryland, MD, USA

    Keshav K Singh, James Russell, Barbara Sigala, Yonggong Zhang & Jerry Williams

  2. Department of Bioscience and Biotechnology, Drexel University, 32nd and Chestnut Streets, Philadelphia, 19104, Pennsylvania, PA, USA

    Kylie F Keshav

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  1. Keshav K Singh
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  2. James Russell
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Singh, K., Russell, J., Sigala, B. et al. Mitochondrial DNA determines the cellular response to cancer therapeutic agents. Oncogene 18, 6641–6646 (1999). https://doi.org/10.1038/sj.onc.1203056

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