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Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport

Oncogene volume 26, pages 5674–5679 (2007)Cite this article

Abstract

A major obstacle to successful chemotherapy is intrinsic or acquired multi-drug resistance (MDR). The most common cause of MDR involves increased drug efflux from cancer cells mediated by members of the ATP-binding cassette (ABC) transporter family. The regulation of ABC transporters in the context of cancer is poorly understood, and clinical efforts to inhibit their function have not been fruitful. Constitutive activation of the Hedgehog (Hh) pathway has been shown to contribute to the growth and maintenance of various cancers. Here, we show that inhibition of Hh signaling increases the response of cancer cells to multiple structurally unrelated chemotherapies. We further show that Hh pathway activation induces chemoresistance in part by increasing drug efflux in an ABC transporter-dependent manner. We found that Hh signaling regulates the expression of the ABC transporter proteins multi-drug resistance protein-1 (MDR1, ABCB1, P-glycoprotein) and (BCRP, ABCG2), and that targeted knockdown of MDR1 and BCRP expression by small interfering RNA partially reverses Hh-induced chemoresistance. These results suggest that the Hh pathway may be a target to overcome MDR and increase chemotherapeutic response.

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Acknowledgements

This work was supported in part by Grants CA89198, CA121551 and P50 CA97007 from the National Institutes of Health/National Cancer Institute; the MD Anderson Cancer Center Esophageal Multidisciplinary Research Project Grant; and grants from the Rivercreek Foundation and the Dallas, Cantu, Smith and Park families. Department of Defence grant PC050508.

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Authors and Affiliations

  1. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Sims-Mourtada & K S C Chao

  2. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J G Izzo

  3. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J G Izzo & J Ajani

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  1. J Sims-Mourtada
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  2. J G Izzo
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Correspondence to K S C Chao.

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

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Sims-Mourtada, J., Izzo, J., Ajani, J. et al. Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 26, 5674–5679 (2007). https://doi.org/10.1038/sj.onc.1210356

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