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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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.
Bennett AF, Buckley PD, Blackwell LF . (1982). Proton release during the pre-steady-state oxidation of aldehydes by aldehyde dehydrogenase. Biochemistry 21: 4407–4413.
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.
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.
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.
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.
Boyd RS, Balkwill FR . (1999). MMP-2 release and activation in ovarian carcinoma: the role of fibroblasts. Br J Cancer 80: 315–321.
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.
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.
Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB . (2008). Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 18: 54–61.
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.
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.
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.
Gatenby RA, Gillies RJ . (2004). Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4: 891–899.
Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ . (2006). Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66: 5216–5223.
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.
Griffiths JR . (1991). Are cancer cells acidic? Br J Cancer 64: 425–427.
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.
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.
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.
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.
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.
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.
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.
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.
Igney FH, Krammer PH . (2002). Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2: 277–288.
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.
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.
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.
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.
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.
Kroemer G, Pouyssegur J . (2008). Tumor cell metabolism: cancer's Achilles′ heel. Cancer Cell 13: 472–482.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Rotin D, Steele-Norwood D, Grinstein S, Tannock IF . (1989). Requirement of the Na+/H+ exchanger for tumor growth. Cancer Res 49: 205–211.
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.
Schornack PA, Gillies RJ . (2003). Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia 5: 135–145.
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.
Stacpoole PW, Owen R, Flotte TR . (2003). The pyruvate dehydrogenase complex as a target for gene therapy. Curr Gene Ther 3: 239–245.
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.
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.
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.
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.
Tannock IF, Rotin D . (1989). Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49: 4373–4384.
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.
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.
Westermarck J, Kahari VM . (1999). Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13: 781–792.
Xu Q, Reed JC . (1998). Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol Cell 1: 337–346.
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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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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DOI: https://doi.org/10.1038/onc.2009.491
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