title: BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function.
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 O(2) 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 (CDeltaBI-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.
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: G-H
authors.initials: GH
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Yan
authors.forename: S-J
authors.initials: SJ
authors.lastname: Shin
authors.forename: S-C
authors.initials: SC
authors.lastname: Hong
authors.forename: T
authors.initials: T
authors.lastname: Ahn
authors.forename: A
authors.initials: A
authors.lastname: Moon
authors.forename: S J
authors.initials: SJ
authors.lastname: Park
authors.forename: Y C
authors.initials: YC
authors.lastname: Lee
authors.forename: W H
authors.initials: WH
authors.lastname: Yoo
authors.forename: H-T
authors.initials: HT
authors.lastname: Kim
authors.forename: D-S
authors.initials: DS
authors.lastname: Kim
authors.forename: S-W
authors.initials: SW
authors.lastname: Chae
authors.forename: H-R
authors.initials: HR
authors.lastname: Kim
authors.forename: H-J
authors.initials: HJ
authors.lastname: Chae
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D005110:Extracellular Space / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D017923:Sodium-Hydrogen Exchangers; D005947:Glucose