Intracellular pH regulation by Na+/H+ exchanger-1 (NHE1) is required for growth factor-induced mammary branching morphogenesis

Developmental Biology

Volumn 365, Issue 1, 2012, Pages 71-81

  Jenkins, Edmund C ^a,b   Debnath, Shawon ^a,b   Gundry, Stephen ^b   Gundry, Sajini ^a   Uyar, Umit ^b   Fata, Jimmie E ^a,b  

^a CITY UNIVERSITY OF NEW YORK   (United States)

^b CITY UNIVERSITY OF NEW YORK   (United States)

Author keywords

Branching morphogenesis; Intracellular pH; Mammary development; NHE1; Sodium hydrogen exchanger; Transforming growth factor alpha

Indexed keywords

5 (N ISOBUTYL N METHYL)AMILORIDE; AMILORIDE; CYTOKERATIN 6; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; SODIUM PROTON EXCHANGE PROTEIN 1; TRANSFORMING GROWTH FACTOR ALPHA;

ALKALINIZATION; ANIMAL TISSUE; ARTICLE; BRANCHING MORPHOGENESIS; BREAST DEVELOPMENT; CELL PH; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME ACTIVITY; MAMMARY GLAND; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REGULATORY MECHANISM;

EID: 84859424210     PISSN: 00121606     EISSN: 1095564X     Source Type: Journal    
DOI: 10.1016/j.ydbio.2012.02.010     Document Type: Article

References (98)

1. Abramoff M.D., Magelhaes P.J., Ram S.J. Image Processing with ImageJ. Biophotonics Int. 2004, 11:36-42.
2. Andersen K., Mori H., Fata J., Bascom J., Oyjord T., Maelandsmo G.M., Bissell M. The metastasis-promoting protein S100A4 regulates mammary branching morphogenesis. Dev. Biol. 2011, 352:181-190.
3. Bianchini L., L'Allemain G., Pouyssegur J. The p42/p44 mitogen-activated protein kinase cascade is determinant in mediating activation of the Na+/H+ exchanger (NHE1 isoform) in response to growth factors. J. Biol. Chem. 1997, 272:271-279.
4. Booth B.W., Smith G.H. Roles of transforming growth factor-alpha in mammary development and disease. Growth Factors 2007, 25:227-235.
5. Bundy L., Wells S., Sealy L. C/EBPbeta-2 confers EGF-independent growth and disrupts the normal acinar architecture of human mammary epithelial cells. Mol. Cancer 2005, 4:43.
6. Busser B., Sancey L., Brambilla E., Coll J.L., Hurbin A. The multiple roles of amphiregulin in human cancer. Biochim. Biophys. Acta 2011, 1816:119-131.
7. Bussolino F., Wang J.M., Turrini F., Alessi D., Ghigo D., Costamagna C., Pescarmona G., Mantovani A., Bosia A. Stimulation of the Na+/H+ exchanger in human endothelial cells activated by granulocyte- and granulocyte-macrophage-colony-stimulating factor. Evidence for a role in proliferation and migration. J. Biol. Chem. 1989, 264:18284-18287.
8. Cardone R.A., Casavola V., Reshkin S.J. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat. Rev. Cancer 2005, 5:786-795.
9. Casey J.R., Grinstein S., Orlowski J. Sensors and regulators of intracellular pH. Nat. Rev. Mol. Cell Biol. 2010, 11:50-61.
10. Chambard J.C., Pouyssegur J. Intracellular pH controls growth factor-induced ribosomal protein S6 phosphorylation and protein synthesis in the G0-G1 transition of fibroblasts. Exp. Cell Res. 1986, 164:282-294.
11. Chiang Y., Chou C.Y., Hsu K.F., Huang Y.F., Shen M.R. EGF upregulates Na+/H+ exchanger NHE1 by post-translational regulation that is important for cervical cancer cell invasiveness. J. Cell. Physiol. 2008, 214:810-819.
12. Counillon L., Franchi A., Pouyssegur J. A point mutation of the Na+/H+ exchanger gene (NHE1) and amplification of the mutated allele confer amiloride resistance upon chronic acidosis. Proc. Natl. Acad. Sci. U. S. A. 1993, 90:4508-4512.
13. Delvaux M., Bastie M.J., Chentoufi J., Cragoe E.J., Vaysse N., Ribet A. Amiloride and analogues inhibit Na(+)-H+ exchange and cell proliferation in AR42J pancreatic cell line. Am. J. Physiol. 1990, 259:G842-G849.
14. Denker S.P., Barber D.L. Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J. Cell Biol. 2002, 159:1087-1096.
15. Dimri G., Band H., Band V. Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Res. 2005, 7:171-179.
16. Ewald A.J., Brenot A., Duong M., Chan B.S., Werb Z. Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev. Cell 2008, 14:570-581.
17. Fata J.E., Werb Z., Bissell M.J. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res. 2004, 6:1-11.
18. Fata J.E., Mori H., Ewald A.J., Zhang H., Yao E., Werb Z., Bissell M.J. The MAPK(ERK-1,2) pathway integrates distinct and antagonistic signals from TGFalpha and FGF7 in morphogenesis of mouse mammary epithelium. Dev. Biol. 2007, 306:193-207.
19. Furukawa O., Matsui H., Suzuki N., Okabe S. Epidermal growth factor protects rat epithelial cells against acid-induced damage through the activation of Na+/H+ exchangers. J. Pharmacol. Exp. Ther. 1999, 288:620-626.
20. Ghishan F.K., Kikuchi K., Riedel B. Epidermal growth factor up-regulates intestinal Na+/H+ exchange activity. Proc. Soc. Exp. Biol. Med. 1992, 201:289-295.
21. Grandin N., Charbonneau M. Cycling of intracellular pH during cell division of Xenopus embryos is a cytoplasmic activity depending on protein synthesis and phosphorylation. J. Cell Biol. 1990, 111:523-532.
22. Grimm S.L., Bu W., Longley M.A., Roop D.R., Li Y., Rosen J.M. Keratin 6 is not essential for mammary gland development. Breast Cancer Res. 2006, 8:R29.
23. Grinstein S., Rotin D., Mason M.J. Na+/H+ exchange and growth factor-induced cytosolic pH changes. Role in cellular proliferation. Biochim. Biophys. Acta 1989, 988:73-97.
24. Gudjonsson T., Adriance M.C., Sternlicht M.D., Petersen O.W., Bissell M.J. Myoepithelial cells: their origin and function in breast morphogenesis and neoplasia. J. Mammary Gland Biol. Neoplasia 2005, 10:261-272.
25. Haimovici J., Beck J.S., Molla-Hosseini C., Vallerand D., Haddad P. Different modulation of hepatocellular Na+/H+ exchange activity by insulin and EGF. Am. J. Physiol. 1994, 267:G364-G370.
26. Harguindey S., Orive G., Luis Pedraz J., Paradiso A., Reshkin S.J. 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 2005, 1756:1-24.
27. Harguindey S., Arranz J.L., Wahl M.L., Orive G., Reshkin S.J. Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res. 2009, 29:2127-2136.
28. Horvat B., Taheri S., Salihagic A. Tumour cell proliferation is abolished by inhibitors of Na+/H+ and HCO3-/Cl- exchange. Eur. J. Cancer 1992, 29A:132-137.
29. Hynes N.E., Watson C.J. Mammary gland growth factors: roles in normal development and in cancer. Cold Spring Harb. Perspect. Biol. 2010, 2:a003186.
30. James-Kracke M.R. Quick and accurate method to convert BCECF fluorescence to pHi: calibration in three different types of cell preparations. J. Cell. Physiol. 1992, 151:596-603.
31. Jang I.S., Brodwick M.S., Wang Z.M., Jeong H.J., Choi B.J., Akaike N. The Na(+)/H(+) exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons. J. Neurochem. 2006, 99:1224-1236.
32. Johnstone E.D., Speake P.F., Sibley C.P. Epidermal growth factor and sphingosine-1-phosphate stimulate Na+/H+ exchanger activity in the human placental syncytiotrophoblast. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 293:R2290-R2294.
33. Khaled A.R., Moor A.N., Li A., Kim K., Ferris D.K., Muegge K., Fisher R.J., Fliegel L., Durum S.K. Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. Mol. Cell. Biol. 2001, 21:7545-7557.
34. Khokha R., Werb Z. Mammary gland reprogramming: metalloproteinases couple form with function. Cold Spring Harb. Perspect. Biol. 2010, 3.
35. Khurana S., Nath S.K., Levine S.A., Bowser J.M., Tse C.M., Cohen M.E., Donowitz M. Brush border phosphatidylinositol 3-kinase mediates epidermal growth factor stimulation of intestinal NaCl absorption and Na+/H+ exchange. J. Biol. Chem. 1996, 271:9919-9927.
36. Kintner D.B., Su G., Lenart B., Ballard A.J., Meyer J.W., Ng L.L., Shull G.E., Sun D. Increased tolerance to oxygen and glucose deprivation in astrocytes from Na(+)/H(+) exchanger isoform 1 null mice. Am. J. Physiol. Cell Physiol. 2004, 287:C12-C21.
37. Kintner D.B., Look A., Shull G.E., Sun D. Stimulation of astrocyte Na+/H+ exchange activity in response to in vitro ischemia depends in part on activation of ERK1/2. Am. J. Physiol. Cell Physiol. 2005, 289:C934-C945.
38. Koliakos G., Paletas K., Kaloyianni M. NHE-1: a molecular target for signalling and cell matrix interactions. Connect. Tissue Res. 2008, 49:157-161.
39. Lagadic-Gossmann D., Huc L., Lecureur V. Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell Death Differ. 2004, 11:953-961.
40. Li Y., Welm B., Podsypanina K., Huang S., Chamorro M., Zhang X., Rowlands T., Egeblad M., Cowin P., Werb Z., Tan L.K., Rosen J.M., Varmus H.E. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc. Natl. Acad. Sci. U. S. A. 2003, 100:15853-15858.
41. Luo J., Kintner D.B., Shull G.E., Sun D. ERK1/2-p90RSK-mediated phosphorylation of Na+/H+ exchanger isoform 1. A role in ischemic neuronal death. J. Biol. Chem. 2007, 282:28274-28284.
42. Ma Y.H., Reusch H.P., Wilson E., Escobedo J.A., Fantl W.J., Williams L.T., Ives H.E. Activation of Na+/H+ exchange by platelet-derived growth factor involves phosphatidylinositol 3'-kinase and phospholipase C gamma. J. Biol. Chem. 1994, 269:30734-30739.
43. Malo M.E., Li L., Fliegel L. Mitogen-activated protein kinase-dependent activation of the Na+/H+ exchanger is mediated through phosphorylation of amino acids Ser770 and Ser771. J. Biol. Chem. 2007, 282:6292-6299.
44. Martin C., Pedersen S.F., Schwab A., Stock C. Intracellular pH gradients in migrating cells. Am. J. Physiol. Cell Physiol. 2011, 300:C490-C495.
45. Matthews H., Ranson M., Kelso M.J. Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: An orally active anti-cancer drug waiting for its call-of-duty?. Int. J. Cancer 2011, 129(9):2051-2061.
46. McCubrey J.A., Steelman L.S., Chappell W.H., Abrams S.L., Wong E.W., Chang F., Lehmann B., Terrian D.M., Milella M., Tafuri A., Stivala F., Libra M., Basecke J., Evangelisti C., Martelli A.M., Franklin R.A. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta 2007, 1773:1263-1284.
47. McLean L.A., Roscoe J., Jorgensen N.K., Gorin F.A., Cala P.M. Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am. J. Physiol. Cell Physiol. 2000, 278:C676-C688.
48. McManus K.J., Hendzel M.J. The relationship between histone H3 phosphorylation and acetylation throughout the mammalian cell cycle. Biochem. Cell Biol. 2006, 84:640-657.
49. McNally S., Martin F. Molecular regulators of pubertal mammary gland development. Ann. Med. 2011, 43:212-234.
50. Meima M.E., Webb B.A., Witkowska H.E., Barber D.L. The sodium-hydrogen exchanger NHE1 is an Akt substrate necessary for actin filament reorganization by growth factors. J. Biol. Chem. 2009, 284:26666-26675.
51. Moolenaar W.H., Tsien R.Y., van der Saag P.T., de Laat S.W. Na+/H+ exchange and cytoplasmic pH in the action of growth factors in human fibroblasts. Nature 1983, 304:645-648.
52. Moor A.N., Fliegel L. Protein kinase-mediated regulation of the Na(+)/H(+) exchanger in the rat myocardium by mitogen-activated protein kinase-dependent pathways. J. Biol. Chem. 1999, 274:22985-22992.
53. Pasic L., Eisinger-Mathason T.S., Velayudhan B.T., Moskaluk C.A., Brenin D.R., Macara I.G., Lannigan D.A. Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue. Genes Dev. 2011, 25:1641-1653.
54. Pedersen S.F. The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death. Pflugers Arch. 2006, 452:249-259.
55. Pedersen S.F., Darborg B.V., Rentsch M.L., Rasmussen M. Regulation of mitogen-activated protein kinase pathways by the plasma membrane Na+/H+ exchanger, NHE1. Arch. Biochem. Biophys. 2007, 462:195-201.
56. Putney L.K., Barber D.L. Na-H exchange-dependent increase in intracellular pH times G2/M entry and transition. J. Biol. Chem. 2003, 278:44645-44649.
57. Putney L.K., Barber D.L. Expression profile of genes regulated by activity of the Na-H exchanger NHE1. BMC Genomics 2004, 5:46.
58. Putney L.K., Denker S.P., Barber D.L. The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. Annu. Rev. Pharmacol. Toxicol. 2002, 42:527-552.
59. Quinn D.A., Dahlberg C.G., Bonventre J.P., Scheid C.R., Honeyman T., Joseph P.M., Thompson B.T., Hales C.A. The role of Na+/H+ exchange and growth factors in pulmonary artery smooth muscle cell proliferation. Am. J. Respir. Cell Mol. Biol. 1996, 14:139-145.
60. Ren B., Deng Y., Mukhopadhyay A., Lanahan A.A., Zhuang Z.W., Moodie K.L., Mulligan-Kehoe M.J., Byzova T.V., Peterson R.T., Simons M. ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish. J. Clin. Invest. 2010, 120:1217-1228.
61. Reshkin S.J., Bellizzi A., Caldeira S., Albarani V., Malanchi I., Poignee M., Alunni-Fabbroni M., Casavola V., Tommasino M. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J. 2000, 14:2185-2197.
62. Santen R.J., Song R.X., McPherson R., Kumar R., Adam L., Jeng M.H., Yue W. The role of mitogen-activated protein (MAP) kinase in breast cancer. J. Steroid Biochem. Mol. Biol. 2002, 80:239-256.
63. Schneider L., Stock C.M., Dieterich P., Jensen B.H., Pedersen L.B., Satir P., Schwab A., Christensen S.T., Pedersen S.F. The Na+/H+ exchanger NHE1 is required for directional migration stimulated via PDGFR-alpha in the primary cilium. J. Cell Biol. 2009, 185:163-176.
64. Schwertfeger K.L. Fibroblast growth factors in development and cancer: insights from the mammary and prostate glands. Curr. Drug Targets 2009, 10:632-644.
65. Shen S.S., Steinhardt R.A. Intracellular pH and the sodium requirement at fertilisation. Nature 1979, 282:87-89.
66. Slepkov E.R., Rainey J.K., Sykes B.D., Fliegel L. Structural and functional analysis of the Na+/H+ exchanger. Biochem. J. 2007, 401:623-633.
67. Smith G.H., Mehrel T., Roop D.R. Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium. Cell Growth Differ. 1990, 1:161-170.
68. Smith G.H., Sharp R., Kordon E.C., Jhappan C., Merlino G. Transforming growth factor-alpha promotes mammary tumorigenesis through selective survival and growth of secretory epithelial cells. Am. J. Pathol. 1995, 147:1081-1096.
69. Steffan J.J., Snider J.L., Skalli O., Welbourne T., Cardelli J.A. Na+/H+ exchangers and RhoA regulate acidic extracellular pH-induced lysosome trafficking in prostate cancer cells. Traffic 2009, 10:737-753.
70. Steffan J.J., Williams B.C., Welbourne T., Cardelli J.A. HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers. J. Cell Sci. 2010, 123:1151-1159.
71. Sternlicht M.D., Sunnarborg S.W. The ADAM17-amphiregulin-EGFR axis in mammary development and cancer. J. Mammary Gland Biol. Neoplasia 2008, 13:181-194.
72. Sternlicht M.D., Sunnarborg S.W., Kouros-Mehr H., Yu Y., Lee D.C., Werb Z. Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin. Development 2005, 132:3923-3933.
73. Sternlicht M.D., Kouros-Mehr H., Lu P., Werb Z. Hormonal and local control of mammary branching morphogenesis. Differentiation 2006, 74:365-381.
74. Stock C., Schwab A. Role of the Na/H exchanger NHE1 in cell migration. Acta Physiol (Oxf.) 2006, 187:149-157.
75. Stock C., Schwab A. Protons make tumor cells move like clockwork. Pflugers Arch. 2009, 458:981-992.
76. Stock C., Gassner B., Hauck C.R., Arnold H., Mally S., Eble J.A., Dieterich P., Schwab A. Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange. J. Physiol. 2005, 567:225-238.
77. Stock C., Cardone R.A., Busco G., Krahling H., Schwab A., Reshkin S.J. Protons extruded by NHE1: digestive or glue?. Eur. J. Cell Biol. 2008, 87:591-599.
78. Strazzabosco M., Poci C., Spirli C., Zsembery A., Granato A., Massimino M.L., Crepaldi G. Intracellular pH regulation in Hep G2 cells: effects of epidermal growth factor, transforming growth factor-alpha, and insulinlike growth factor-II on Na+/H+ exchange activity. Hepatology 1995, 22:588-597.
79. Stull M.A., Wood T.L. Expression of the IGFs, IGF-IR and IGFBPs in the normal mammary gland and breast. Breast Dis. 2003, 17:15-26.
80. Stuwe L., Muller M., Fabian A., Waning J., Mally S., Noel J., Schwab A., Stock C. pH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solution. J. Physiol. 2007, 585:351-360.
81. Svegliati-Baroni G., Di Sario A., Casini A., Ferretti G., D'Ambrosio L., Ridolfi F., Bolognini L., Salzano R., Orlandi F., Benedetti A. The Na+/H+ exchanger modulates the fibrogenic effect of oxidative stress in rat hepatic stellate cells. J. Hepatol. 1999, 30:868-875.
82. Takahashi E., Abe J., Gallis B., Aebersold R., Spring D.J., Krebs E.G., Berk B.C. p90(RSK) is a serum-stimulated Na+/H+ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of Na+/H+ exchanger isoform-1. J. Biol. Chem. 1999, 274:20206-20214.
83. Thomas J.A., Buchsbaum R.N., Zimniak A., Racker E. Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ. Biochemistry 1979, 18:2210-2218.
84. Tominaga T., Barber D.L. Na-H exchange acts downstream of RhoA to regulate integrin-induced cell adhesion and spreading. Mol. Biol. Cell 1998, 9:2287-2303.
85. Tominaga T., Ishizaki T., Narumiya S., Barber D.L. p160ROCK mediates RhoA activation of Na-H exchange. EMBO J. 1998, 17:4712-4722.
86. Tsuta K., Liu D.C., Kalhor N., Wistuba I.I., Moran C.A. Using the mitosis-specific marker anti-phosphohistone H3 to assess mitosis in pulmonary neuroendocrine carcinomas. Am. J. Clin. Pathol. 2011, 136:252-259.
87. Turturro F., Friday E., Fowler R., Surie D., Welbourne T. Troglitazone acts on cellular pH and DNA synthesis through a peroxisome proliferator-activated receptor gamma-independent mechanism in breast cancer-derived cell lines. Clin. Cancer Res. 2004, 10:7022-7030.
88. Van Lookeren Campagne M.M., Aerts R.J., Spek W., Firtel R.A., Schaap P. Cyclic-AMP-induced elevation of intracellular pH precedes, but does not mediate, the induction of prespore differentiation in Dictyostelium discoideum. Development 1989, 105:401-406.
89. von Lintig F.C., Dreilinger A.D., Varki N.M., Wallace A.M., Casteel D.E., Boss G.R. Ras activation in human breast cancer. Breast Cancer Res. Treat. 2000, 62:51-62.
90. Wakabayashi I., Poteser M., Groschner K. Intracellular pH as a determinant of vascular smooth muscle function. J. Vasc. Res. 2006, 43:238-250.
91. Wang Y., Luo J., Chen X., Chen H., Cramer S.W., Sun D. Gene inactivation of Na+/H+ exchanger isoform 1 attenuates apoptosis and mitochondrial damage following transient focal cerebral ischemia. Eur. J. Neurosci. 2008, 28:51-61.
92. Webb D.J., Nuccitelli R. Direct measurement of intracellular pH changes in Xenopus eggs at fertilization and cleavage. J. Cell Biol. 1981, 91:562-567.
93. Wickenden J.A., Watson C.J. Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts. Breast Cancer Res. 2010, 12:202.
94. Wiseman B.S., Sternlicht M.D., Lund L.R., Alexander C.M., Mott J., Bissell M.J., Soloway P., Itohara S., Werb Z. Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J. Cell Biol. 2003, 162:1123-1133.
95. Woodward T.L., Xie J.W., Haslam S.Z. The role of mammary stroma in modulating the proliferative response to ovarian hormones in the normal mammary gland. J. Mammary Gland Biol. Neoplasia 1998, 3:117-131.
96. Yan W., Nehrke K., Choi J., Barber D.L. The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor. J. Biol. Chem. 2001, 276:31349-31356.
97. Yang X., Wang D., Dong W., Song Z., Dou K. Inhibition of Na(+)/H(+) exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility. Cancer Lett. 2010, 295:198-204.
98. Yang X., Wang D., Dong W., Song Z., Dou K. Suppression of Na(+)/H (+) exchanger 1 by RNA interference or amiloride inhibits human hepatoma cell line SMMC-7721 cell invasion. Med. Oncol. 2011, 28:385-390.