Abstract
Recent findings indicate that (a) mitochondria in proliferating cancer cells are functional, (b) cancer cells use more oxygen than normal cells for oxidative phosphorylation, and (c) cancer cells critically rely on cytosolic NADH transported into mitochondria via the malate-aspartate shuttle (MAS) for ATP production. In a spontaneous lung cancer model, tumor growth was reduced by 50% in heterozygous oxoglutarate carrier (OGC) knock-out mice compared with wild-type counterparts. To determine the mechanism through which OGC promotes tumor growth, the effects of the OGC inhibitor N-phenylmaleimide (NPM) on mitochondrial activity, oxygen consumption, and ATP production were evaluated in melanoma cell lines. NPM suppressed oxygen consumption and decreased ATP production in melanoma cells in a dose-dependent manner. NPM also reduced the proliferation of melanoma cells. To test the effects of NPM on tumor growth and metastasis in vivo, NPM was administered in a human melanoma xenograft model. NPM reduced tumor growth by approximately 50% and reduced melanoma invasion by 70% at a dose of 20 mg/kg. Therefore, blocking OGC activity may be a useful approach for cancer therapy.
Highlights
We reported that up to 80% of the total ATP production in melanoma and lung cancer cells [1], and about 40% of the ATP production in pancreatic cancer cells [2,3], depends on cytosolic NADH and the malate-aspartate shuttle (MAS)
The oxoglutarate carrier (OGC) inhibitor NPT was used to test whether OGC inhibition could block the MAS, reduce ATP production, and inhibit cancer growth [13]
These residues involved in the interaction of OGC with NPM are likely essential for transport function and conformational changes
Summary
We reported that up to 80% of the total ATP production in melanoma and lung cancer cells [1], and about 40% of the ATP production in pancreatic cancer cells [2,3], depends on cytosolic NADH and the malate-aspartate shuttle (MAS). The MAS transfers cytosolic NADH into mitochondria for ATP production through oxidative phosphorylation (OxPhos) in the mitochondrial membrane [1]. Knock-down of OGC reduced ATP production by 80% and inhibited the growth of lung and melanoma cancer cells by over 90% [1]. Blocking OGC may selectively inhibit cancer growth by reducing ATP production in cancer cells because cancer cells rely on the MAS for ATP generation while normal cells do not [1,2]
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