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Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

Oncogene volume 28, pages 3689–3701 (2009)Cite this article

Abstract

ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

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Acknowledgements

We thank Dr Ivor Benjamin for the HSF1 MEFs; Dr Jianrong Lu, Dr Adam Riker and Dr Laurie Owen for reading the article; Ms Amy Brown for editorial assistance; Dr June Ayling, Dr Robert Laush and Ms Judy Miller for assistance with equipments. We are grateful for the support from The Vincent F Kilborn, Jr. Cancer Research Foundation (M Tan) and from the Radiumhospitalets Legater Award Project 334003 (M Tan and O Fodstad).

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Author notes

  1. Y H Zhao and M Zhou: These authors contributed equally to this work.

  2. M Tan: M Tan is a Vincent F Kilborn, Jr Cancer Research Scholar.

Authors and Affiliations

  1. Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA

    Y H Zhao, M Zhou, H Liu, Y Ding, H T Khong, O Fodstad & M Tan

  2. Department of Biochemistry and Molecular Biology, West China Medical Center, Sichuan University, Chengdu, China

    Y H Zhao

  3. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D Yu

  4. Institute for Cancer Research, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway

    O Fodstad

  5. Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, AL, USA

    M Tan

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  1. Y H Zhao
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Correspondence to M Tan.

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

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Zhao, Y., Zhou, M., Liu, H. et al. Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene 28, 3689–3701 (2009). https://doi.org/10.1038/onc.2009.229

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