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 þ , 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 (CDBI-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.

Enhanced Lysosomal Activity Is Involved in Bax Inhibitor-1-induced Regulation of the Endoplasmic Reticulum (ER) Stress Response and Cell Death against ER Stress

“…The question remains as to how BI-1 induces increases in lysosomal V-ATPase activity. We recently showed that the acidic environment in BI-1 cells is related to mitochondrial dysfunction (41). Increased glucose anaerobic metabolism, leading to H ϩ production, sodium hydrogen exchanger activity, and lactate production, has also been demonstrated in BI-1 cells.…”

“…Another function, the Ca 2ϩ leak channel-like effect of BI-1 on the ER (11,15), affects cationic balance through continuous leakage of Ca 2ϩ from the ER. The Ca 2ϩ dynamically active status of BI-1 cells may activate the intracellular Ca 2ϩ /H ϩ antiporter and other H ϩ -associated transporter systems (41,42). Increasing cytoplasmic H ϩ may activate lysosomal V-ATPase for intracellular pH homeostasis in BI-1 cells (Fig.…”

Bax Inhibitor 1 in apoptosis and disease

“…Tumour development is promoted by the formation of a patho-physiological microenvironment characterised by hypoxic conditions, nutrient deprivation and acidification. This acidic environment is regulated by ion channels and transporters, for example, Na þ /H þ (NHE) or Cl/HCO 3 exchangers (Plopper et al, 1995;Lee et al, 2010b). Elevated NHE levels enhance the acidification of extracellular space by extruding excess protons from tumour cells (Tannock and Rotin, 1989;Wahl et al, 2000), which by activating proteases for example, can promote the invasiveness of carcinoma cells (Reshkin et al, 2000;Lee et al, 2010b).…”

“…This acidic environment is regulated by ion channels and transporters, for example, Na þ /H þ (NHE) or Cl/HCO 3 exchangers (Plopper et al, 1995;Lee et al, 2010b). Elevated NHE levels enhance the acidification of extracellular space by extruding excess protons from tumour cells (Tannock and Rotin, 1989;Wahl et al, 2000), which by activating proteases for example, can promote the invasiveness of carcinoma cells (Reshkin et al, 2000;Lee et al, 2010b). BI-1 overexpression has been shown to increase glucose uptake, causing downregulation of pyruvate dehydrogenase activity and accumulation of lactate inducing acidification, through an as yet unknown mechanism.…”

“…BI-1 overexpression has been shown to increase glucose uptake, causing downregulation of pyruvate dehydrogenase activity and accumulation of lactate inducing acidification, through an as yet unknown mechanism. These metabolic changes promoted tumourigenic cells to take up glucose and convert it to lactate, despite being in an oxygenated environment (Lee et al, 2010b). Moreover, BI-1 overexpression increased cell motility and invasiveness imposing an increased acid load on tumour cells, with this surplus removed by NHE, resulting in extracellular acidification.…”