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Regulation of breast tumorigenesis through acid sensors

Oncogene volume 35, pages 4102–4111 (2016)Cite this article

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Abstract

The low extracellular pH in the microenvironment has been shown to promote tumor growth and metastasis; however, the underlying mechanism is poorly understood. Particularly, little is known how the tumor cell senses the acidic signal to activate the acidosis-mediated signaling. In this study, we show that breast cancer cells express acid-sensing ion channel 1 (ASIC1), a proton-gated cation channel primarily expressed in the nervous system. RNA interference, knockout and rescue experiments demonstrate a critical role for ASIC1 in acidosis-induced reactive oxidative species and NF-κB activation, two key events for tumorigenesis. Mechanistically, ASIC1 is required for acidosis-mediated signaling through calcium influx. We show that as a cytoplasmic membrane protein, ASIC1 is also associated with mitochondria, suggesting that ASIC1 may regulate mitochondrial calcium influx. Importantly, interrogation of the Cancer Genome Atlas breast invasive carcinoma data set indicates that alterations of ASIC1 alone or combined with other 4 ASIC genes are significantly correlated with poor patient survival. Furthermore, ASIC1 inhibitors cause a significant reduction of tumor growth and tumor load. Together, these results suggest that ASIC1 contributes to breast cancer pathogenesis in response to acidic tumor microenvironments, and ASIC1 may serve as a prognostic marker and a therapeutic target for breast cancer.

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Acknowledgements

We thank Dr Parminder J.S. Vig at UMMC for providing mouse brain tissues. This work is supported in part by a grant from the National Institutes of Health R01 CA154989 (YM) and a grant from UMMC’s Intramural Research Support Program (SCG). Imaging Core of Center for Psychiatric Neuroscience at UMMC is supported by COBRE grant GM103328.

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Author notes

  1. S C Gupta

    Present address: 6Current address: Department of Biochemistry, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India.,

Authors and Affiliations

  1. Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA

    S C Gupta, R Singh, M Asters, J Liu & Y-Y Mo

  2. Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA

    S C Gupta & R Singh

  3. Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, USA

    X Zhang

  4. Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA

    M R Pabbidi & Y-Y Mo

  5. Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, USA

    K Watabe

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Correspondence to Y-Y Mo.

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Gupta, S., Singh, R., Asters, M. et al. Regulation of breast tumorigenesis through acid sensors. Oncogene 35, 4102–4111 (2016). https://doi.org/10.1038/onc.2015.477

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