Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Alrefai WA, Scaglione-Sewell B, Tyagi S, Wartman L, Brasitus TA, Ramaswamy K et al. (2001). Differential regulation of the expression of Na(+)/H(+) exchanger isoform NHE3 by PKC-alpha in Caco-2 cells. Am J Physiol Cell Physiol 281: C1551–C1558.

    Article  CAS  PubMed  Google Scholar 

  • Bennett AF, Buckley PD, Blackwell LF . (1982). Proton release during the pre-steady-state oxidation of aldehydes by aldehyde dehydrogenase. Biochemistry 21: 4407–4413.

    Article  CAS  PubMed  Google Scholar 

  • Bereiter-Hahn J, Voth M . (1988). Ionic control of locomotion and shape of epithelial cells: II. Role of monovalent cations Cell Motil Cytoskeleton 10: 528–536.

    Article  CAS  PubMed  Google Scholar 

  • Bhujwalla ZM, Artemov D, Ballesteros P, Cerdan S, Gillies RJ, Solaiyappan M . (2002). Combined vascular and extracellular pH imaging of solid tumors. NMR Biomed 15: 114–119.

    Article  CAS  PubMed  Google Scholar 

  • Bolduc N, Brisson LF . (2002). Antisense down regulation of NtBI-1 in tobacco BY-2 cells induces accelerated cell death upon carbon starvation. FEBS Lett 532: 111–114.

    Article  CAS  PubMed  Google Scholar 

  • Bourguignon LY, Singleton PA, Diedrich F, Stern R, Gilad E . (2004). CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. J Biol Chem 279: 26991–27007.

    Article  CAS  PubMed  Google Scholar 

  • Boyd RS, Balkwill FR . (1999). MMP-2 release and activation in ovarian carcinoma: the role of fibroblasts. Br J Cancer 80: 315–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chae HJ, Kim HR, Xu C, Bailly-Maitre B, Krajewska M, Krajewski S et al. (2004). BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol Cell 15: 355–366.

    Article  CAS  PubMed  Google Scholar 

  • Chen EI, Hewel J, Krueger JS, Tiraby C, Weber MR, Kralli A . (2007). Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res 67: 1472–1486.

    Article  CAS  PubMed  Google Scholar 

  • Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB . (2008). Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 18: 54–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dohm CP, Siedenberg S, Liman J, Esposito A, Wouters FS, Reed JC et al. (2006). Bax inhibitor-1 protects neurons from oxygen-glucose deprivation. J Mol Neurosci 29: 1–8.

    Article  CAS  PubMed  Google Scholar 

  • Denker SP, Barber DL . (2002). Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol 159: 1087–1096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Del Carmen, Garcia, Molina, Wolgien M, da Silva ID, Villanova FE et al. (2005). Differential gene expression assessed by cDNA microarray analysis in breast cancer tissue under tamoxifen treatment. Eur J Gynaecol Oncol 26: 501–504.

    Google Scholar 

  • Gatenby RA, Gillies RJ . (2004). Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4: 891–899.

    Article  CAS  PubMed  Google Scholar 

  • Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ . (2006). Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66: 5216–5223.

    Article  CAS  PubMed  Google Scholar 

  • Gillies RJ, Martinez-Zaguilan R, Martinez GM, Serrano R, Perona R . (1990). Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions. Proc Natl Acad Sci USA 87: 7414–7418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griffiths JR . (1991). Are cancer cells acidic? Br J Cancer 64: 425–427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grinstein S, Woodside M, Waddell TK, Downey GP, Orlowski J, Pouyssegur J et al. (1993). Focal localization of the NHE-1 isoform of the Na+/H+ antiport: assessment of effects on intracellular pH. EMBO J 12: 5209–5218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grzmil M, Thelen P, Hemmerlein B, Schweyer S, Voigt S, Mury D et al. (2003). Bax inhibitor-1 is overexpressed in prostate cancer and its specific down-regulation by RNA interference leads to cell death in human prostate carcinoma cells. Am J Pathol 163: 543–552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grzmil M, Kaulfuss S, Thelen P, Hemmerlein B, Schweyer S, Obenauer S et al. (2006). Expression and functional analysis of Bax inhibitor-1 in human breast cancer cells. J Pathol 208: 340–349.

    Article  CAS  PubMed  Google Scholar 

  • Harima Y, Togashi A, Horikoshi K, Imamura M, Sougawa M, Sawada S et al. (2004). Prediction of outcome of advanced cervical cancer to thermoradiotherapy according to expression profiles of 35 genes selected by cDNA microarray analysis. Int J Radiat Oncol Biol Phys 60: 237–248.

    Article  CAS  PubMed  Google Scholar 

  • Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ . (2005). The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin-one single nature. Biochim Biophys Acta 1756: 1–24.

    CAS  PubMed  Google Scholar 

  • Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK . (2002). Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res 8: 1284–1291.

    CAS  PubMed  Google Scholar 

  • Hille C, Walz B . (2007). A vacuolar-type H+-ATPase and a Na+/H+ exchanger contribute to intracellular pH regulation in cockroach salivary ducts. J Exp Biol 210: 1463–1471.

    Article  CAS  PubMed  Google Scholar 

  • Honegger KJ, Capuano P, Winter C, Bacic D, Stange G, Wagner CA et al. (2006). Regulation of sodium-proton exchanger isoform 3 (NHE3) by PKA and exchange protein directly activated by cAMP (EPAC). Proc Natl Acad Sci USA 103: 803–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Igney FH, Krammer PH . (2002). Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2: 277–288.

    Article  CAS  PubMed  Google Scholar 

  • Jones LE, Humphreys MJ, Campbell F, Neoptolemos JP, Boyd MT . (2004). Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer: increased expression of matrix metalloproteinase-7 predicts poor survival. Clin Cancer Res 10: 2832–2845.

    Article  CAS  PubMed  Google Scholar 

  • Kaplan D, Boron W . (1994). Long-term expression of c-H-ras stimulates Na-H and Na(+)-dependent Cl-/HCO3 exchange in NIH-3T3 fibroblasts. J Biol Chem 269: 4116–4124.

    CAS  PubMed  Google Scholar 

  • Kim HR, Lee GH, Ha KC, Ahn T, Moon JY, Lee BJ et al. (2008). Bax Inhibitor-1 Is a pH-dependent regulator of Ca2+ channel activity in the endoplasmic reticulum. J Biol Chem 283: 15946–15955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim MS, Lee EJ, Kim HR, Moon A . (2003). p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res 63: 5454–5461.

    CAS  PubMed  Google Scholar 

  • Klein M, Seeger P, Schuricht B, Alper SL, Schwab A . (2000). Polarization of Na(+)/H(+) and Cl(−)/HCO (3)(−) exchangers in migrating renal epithelial cells. J General Physiol 115: 599–607.

    Article  CAS  Google Scholar 

  • Kroemer G, Pouyssegur J . (2008). Tumor cell metabolism: cancer's Achilles′ heel. Cancer Cell 13: 472–482.

    Article  CAS  PubMed  Google Scholar 

  • Lagarde AE, Franchis AJ, Paris S, Poyssegur JM . (1988). Effect of mutations affecting Na+: H+ antiport activity on tumorigenic potential of hamster lung fibroblasts. J Cell Biochem 36: 249–260.

    Article  CAS  PubMed  Google Scholar 

  • Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ . (2008). Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem 283: 28106–28114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee-Kwon W, Kim JH, Choi JW, Kawano K, Cha B, Dartt DA et al. (2003). Ca2+-dependent inhibition of NHE3 requires PKC alpha which binds to E3KARP to decrease surface NHE3 containing plasma membrane complexes. Am J Physiol Cell Physiol 285: C1527–C1536.

    Article  CAS  PubMed  Google Scholar 

  • McLean LA, Roscoe J, Jørgensen NK, Gorin FA, Cala PM . (2000). Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am J Physiol Cell Physiol 278: C676–C688.

    Article  CAS  PubMed  Google Scholar 

  • Plopper GE, McNamee HP, Dike LE, Bojanowski K, Ingber DE . (1995). Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell 6: 1349–1365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Provent P, Benito M, Hiba B, Farion R, López-Larrubia P, Ballesteros P et al. (2007). Serial in vivo spectroscopic nuclear magnetic resonance imaging of lactate and extracellular pH in rat gliomas shows redistribution of protons away from sites of glycolysis. Cancer Res 67: 7638–7645.

    Article  CAS  PubMed  Google Scholar 

  • Putney LK, Denker SP, Barber DL . (2002). The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. Annu Rev Pharmacol Toxicol 42: 527–552.

    Article  CAS  PubMed  Google Scholar 

  • Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M et al. (2000). Na+/H+ exchangerdependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J 14: 2185–2197.

    Article  CAS  PubMed  Google Scholar 

  • Rofstad EK, Mathiesen B, Kindem K, Galappathi K . (2006). Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res 66: 6699–6707.

    Article  CAS  PubMed  Google Scholar 

  • Rotin D, Steele-Norwood D, Grinstein S, Tannock IF . (1989). Requirement of the Na+/H+ exchanger for tumor growth. Cancer Res 49: 205–211.

    CAS  PubMed  Google Scholar 

  • Rosengren S, Henson PM, Worthen GS . (1994). Migration-associated volume changes in neutrophils facilitate the migratory process in vitro. Am J Physiol 267: 1623–C1632.

    Article  Google Scholar 

  • Schornack PA, Gillies RJ . (2003). Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia 5: 135–145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saadoun S, Papadopoulos MC, Hara-Chikuma M, Verkman AS . (2005). Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature 434: 786–792.

    Article  CAS  PubMed  Google Scholar 

  • Stacpoole PW, Owen R, Flotte TR . (2003). The pyruvate dehydrogenase complex as a target for gene therapy. Curr Gene Ther 3: 239–245.

    Article  CAS  PubMed  Google Scholar 

  • Stephens FB, Constantin-Teodosiu D, Greenhaff PL . (2007). New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol 581: 431–444.

    Article  PubMed  PubMed Central  Google Scholar 

  • Steffan JJ, Snider JL, Skalli O, Welbourne T, Cardelli JA . (2009). Na+/H+ exchangers and RhoA regulate acidic extracellular pH-induced lysosome trafficking in prostate cancer cells. Traffic 10: 737–753.

    Article  CAS  PubMed  Google Scholar 

  • Stellingwerff T, Watt MJ, Heigenhauser GJ, Spriet LL . (2003). Effects of reduced free fatty acid availability on skeletal muscle PDH activation during aerobic exercise. Pyruvate dehydrogenase. Am J Physiol Endocrinol Metab 284: E589–E596.

    Article  CAS  PubMed  Google Scholar 

  • Schmalfeldt B, Prechtel D, Härting K, Späthe K, Rutke S, Konik E et al. (2001). Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer. Clin Cancer Res 7: 2396–2404.

    CAS  PubMed  Google Scholar 

  • Tannock IF, Rotin D . (1989). Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49: 4373–4384.

    CAS  PubMed  Google Scholar 

  • Thomas SH, Wagner RD, Arakaki AK, Skolnick J, Kirby JR, Shimkets LJ et al. (2008). The mosaic genome of Anaeromyxobacter dehalogenans strain 2CP-C suggests an aerobic common ancestor to the delta-proteobacteria. PLoS ONE 3: e2103.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wahl ML, Pooler PM, Briand P, Leeper DB, Owen CS . (2000). Intracellular pH regulation in a nonmalignant and a derived malignant human breast cell line. J Cell Physiol 183: 373–380.

    Article  CAS  PubMed  Google Scholar 

  • Westermarck J, Kahari VM . (1999). Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13: 781–792.

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Reed JC . (1998). Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol Cell 1: 337–346.

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

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

Authors
  1. G-H Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S-J Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S-C Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S J Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y C Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W H Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H-T Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D-S Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S-W Chae
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H-R Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. H-J Chae
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

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

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.491

Keywords

This article is cited by

Search

Advanced search

Quick links