BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function.
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.
Lee
G-H
GH
Department of Pharmacology and Cardiovascular Research Center, Chonbuk National University, Jeonju, Republic of Korea.
Yan
C
C
Shin
S-J
SJ
Hong
S-C
SC
Ahn
T
T
Moon
A
A
Park
S J
SJ
Lee
Y C
YC
Yoo
W H
WH
Kim
H-T
HT
Kim
D-S
DS
Chae
S-W
SW
Kim
H-R
HR
Chae
H-J
HJ
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*
D051017:Apoptosis Regulatory Proteins; D017923:Sodium-Hydrogen Exchangers; D005947:Glucose