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Identification of midkine as a mediator for intercellular transfer of drug resistance

Oncogene volume 24, pages 4965–4974 (2005)Cite this article

Abstract

Resistance to cytotoxic agents is a major limitation for their clinical use to treat human cancers. Tumors become resistant to chemotherapy when a subset of cells undergoes molecular changes leading to overexpression of drug transport proteins, alterations in drug–target interactions or reduced ability to commit apoptosis. However, such changes may not be sufficient to explain why both resistant and nonresistant cells survive drug's action in tumors that ultimately become drug resistant. We hypothesized that, in such tumors, a cytoprotective relationship may exist between drug-resistant and neighboring drug-sensitive cells. The present study addresses the possibility that drug-resistant cells secrete in their culture medium factors able to protect sensitive cells from drug toxicity. A survival molecule, midkine, was identified by cDNA array to be expressed only in drug-resistant cells. Midkine-enriched fractions obtained by affinity chromatography exert a significant cytoprotective effect against doxorubicin in the wild-type drug-sensitive cells. Moreover, transfection of these cells with the midkine gene caused a decreased response to doxorubicin. The underlying mechanism of this cytoprotection appeared to imply activation of the Akt pathway and inhibition of drug-induced proliferation arrest as well as apoptotic cell death. These findings provide evidence for the existence of intercellular cytoprotective signals such as the one mediated by midkine, originating from cells with acquired drug resistance to protect neighboring drug-sensitive cells and thus contribute to development of resistance to chemotherapy.

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Acknowledgements

This investigation was supported in part by grants from the National Cancer Institute – NIH (No. 1R01 CA096616-01A1), John W Anderson Foundation, North Suburban Medical Research Junior Board, Medical Research Junior Board Foundation, Medical Research Institute Council, R Wile Foundation, and the Children's Memorial Research Center Program in Cancer Biology and Chemotherapy. We express our appreciation to Dr Eric G Bremer for allowing the use of the Quantitative RT–PCR machine, and Ms Roberta Gerard and Mr William Goossens for their excellent assistance in preparation of the manuscript and all illustrations, respectively.

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Authors and Affiliations

  1. Children's Memorial Research Center (CMRC), Cancer Biology Program, Chicago, IL, USA

    Bernard L Mirkin, Sandra Clark, Xin Zheng, Fei Chu & Abdelhadi Rebbaa

  2. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, 60614, IL, USA

    Bernard L Mirkin & Abdelhadi Rebbaa

  3. Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, 60614, IL, USA

    Bernard L Mirkin

  4. Program in Neurobiology and Behavior, University of Washington, Seattle, 98195, WA, USA

    Bryan D White

  5. Ben May Institute for Cancer Research, University of Chicago, Chicago, 60637, IL, USA

    Marianne Greene

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  1. Bernard L Mirkin
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  2. Sandra Clark
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Correspondence to Abdelhadi Rebbaa.

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Supplementary information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Mirkin, B., Clark, S., Zheng, X. et al. Identification of midkine as a mediator for intercellular transfer of drug resistance. Oncogene 24, 4965–4974 (2005). https://doi.org/10.1038/sj.onc.1208671

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