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BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function

Oncogene volume 29, pages 2130–2141 (2010)Cite this article

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A Corrigendum to this article was published on 11 February 2016

Abstract

The anti-apoptotic protein, BAX inhibitor-1 (BI-1), has a role in cancer/tumor progression. BI-1-overexpressing HT1080 and B16F10 cells produced higher lung weights and tumor volumes after injection into the tail veins of mice. Transfection of BI-1 siRNA into cells before injection blocked lung metastasis. in vitro, the overexpression of BI-1 increased cell mobility and invasiveness, with highly increased glucose consumption and cytosolic accumulation of lactate and pyruvate, but decreased mitochondrial O2 consumption and ATP production. Glucose metabolism-associated extracellular pH also decreased as cells excreted more H+, and sodium hydrogen exchanger (NHE) activity increased, probably as a homeostatic mechanism for intracellular pH. These alterations activated MMP 2/9 and cell mobility and invasiveness, which were reversed by the NHE inhibitor, 5-(N-ethyl-N-isopropyl) amiloride (EIPA), suggesting a role for NHE in cancer metastasis. In both in vitro and in vivo experiments, C-terminal deleted (CΔBI-1) cells showed similar results to control cells, suggesting that the C-terminal motif is required for BI-1-associated alterations of glucose metabolism, NHE activation and cancer metastasis. These findings strongly suggest that BI-1 reduces extracellular pH and regulates metastasis by altering glucose metabolism and activating NHE, with the C-terminal tail having a pivotal role in these processes.

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Acknowledgements

This study was supported by the Research Program for New Drug Target Discovery grant from the Ministry of Education, Science and Technology, South Korea and partly supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A084144).

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Authors and Affiliations

  1. Department of Pharmacology and Cardiovascular Research Center, Chonbuk National University, Jeonju, Republic of Korea

    G-H Lee, C Yan, D-S Kim, S-W Chae & H-J Chae

  2. Research Center for Pulmonary Disorder, Chonbuk National University Hospital, Jeonju, Republic of Korea

    G-H Lee, S J Park, Y C Lee, W H Yoo & H-J Chae

  3. Department of Microbiology, School of Medicine, Chonbuk National University, Jeonju, Republic of Korea

    S-J Shin & S-C Hong

  4. Department of Biochemistry, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea

    T Ahn

  5. Pharmacy School, Duksung Women’s University, Seoul, Republic of Korea

    A Moon

  6. Department of Internal Medicine and Airway Remodeling Laboratory, School of Medicine, Chonbuk National University, Jeonju, Republic of Korea

    S J Park & Y C Lee

  7. Division of Rheumatology, Department of Internal Medicine, Chonbuk National University, Jeonju, Republic of Korea

    W H Yoo

  8. Department of Anatomy, School of Medicine, Chonbuk National University, Jeonju, Republic of Korea

    H-T Kim

  9. Department of Dental Pharmacology, School of Dentistry, Wonkwang University, Iksan, Chonbuk, Republic of Korea

    H-R Kim

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Correspondence to H-R Kim or H-J Chae.

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

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Lee, GH., Yan, C., Shin, SJ. et al. BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function. Oncogene 29, 2130–2141 (2010). https://doi.org/10.1038/onc.2009.491

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