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HRG-1 enhances cancer cell invasive potential and couples glucose metabolism to cytosolic/extracellular pH gradient regulation by the vacuolar-H+ ATPase

Oncogene volume 33, pages 4653–4663 (2014)Cite this article

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Abstract

Haeme-responsive gene (HRG)-1 encodes a 16-kDa transmembrane protein that is induced by insulin-like growth factor-1 (IGF-1) and associates with the vacuolar-(H+) ATPase (V-ATPase). We previously reported that HRG-1 is essential for V-ATPase activity in endosomal acidification and receptor trafficking. Here, we show that in highly invasive and migratory cancer cell lines, HRG-1 and the V-ATPase are co-expressed at the plasma membrane, whereas in less invasive cell lines and non-transformed cells HRG-1 over-expression remains confined to intracellular compartments. Stable suppression of HRG-1 in invasive breast cancer MDA-MB-231 cells decreases extracellular pH, cell growth, migration and invasion. Ectopic expression of HRG-1 in non-invasive MCF-7 cells enhances V-ATPase activity, lowers the extracellular pH and increases the pH-dependent activity of MMP2 and MMP9 matrix metalloproteinases. HRG-1 enhances trafficking of the glucose transporter-1 (GLUT-1) with a concomitant increase in glucose uptake and lactate production. HRG-1 also promotes trafficking of the insulin-like growth factor I receptor (IGF-1R), β1-integrin and IGF-1 signalling. Taken together, our findings indicate that HRG-1 expression at the plasma membrane enhances V-ATPase activity, drives glycolytic flux and facilitates cancer cell growth, migration and invasion. Thus, HRG-1 may represent a novel target for selectively disrupting V-ATPase activity and the metastatic potential of cancer cells.

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Acknowledgements

We are grateful to our colleagues in the Cell Biology Laboratory and Dr Kellie Dean for helpful discussions, and to Kurt Tidmore for preparing illustrations. This work was supported by the Health Research Board (PhD Scholars Programme in Cancer Biology (FF)) and Science Foundation Ireland (PI Award: 06/INI/B107).

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Author notes

  1. V Ayllon

    Present address: 3Current address: Pfizer—Universidad de Granada—Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, Spain.,

Authors and Affiliations

  1. Cell Biology Laboratory, University College Cork, BioSciences Institute, College Road, Cork, Ireland

    F M Fogarty, J O'Keeffe, V Ayllon & R O'Connor

  2. Department of Biochemistry, Laboratory of Biophysics and Bioanalysis, University College Cork, BioSciences Institute, College Road, Cork, Ireland

    A Zhadanov & D Papkovsky

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  1. F M Fogarty
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Correspondence to R O'Connor.

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Fogarty, F., O'Keeffe, J., Zhadanov, A. et al. HRG-1 enhances cancer cell invasive potential and couples glucose metabolism to cytosolic/extracellular pH gradient regulation by the vacuolar-H+ ATPase. Oncogene 33, 4653–4663 (2014). https://doi.org/10.1038/onc.2013.403

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