C75, An inhibitor of fatty acid synthase, suppresses the mitochondrial fatty acid synthesis pathway and impairs mitochondrial function [Cell Biology]

May 1st, 2014 by Chen, C., Han, X., Zou, X., Li, Y., Yang, L., Cao, K., Xu, J., Long, J., Liu, J., Feng, Z.

C75 (4-methylene-2-octyl-5-oxotetra- hydrofuran-3-carboxylic acid) is a synthetic fatty acid synthase (FASN) inhibitor with potential therapeutic effects in several cancer models. Mitochondrial β-ketoacyl-acyl carrier protein synthase (HsmtKAS) is a key enzyme in the newly discovered mitochondrial fatty acid synthesis pathway (mtFAS II) that can produce the substrate for lipoic acid (LA) synthesis. HsmtKAS shares conserved catalytic domains with FASN, which are responsible for binding to C75. In our study, we explored the possible effect of C75 on HsmtKAS and mitochondrial function. C75 treatment decreased LA content, impaired mitochondrial function, increased content of reactive oxygen species (ROS) and reduced cell viability. HsmtKAS but not FASN knockdown had an effect that was similar to C75 treatment. Meanwhile, an LA supplement efficiently inhibited C75-induced mitochondrial dysfunction and oxidative stress. Overexpression of HsmtKAS showed cellular protection against low dose C75 addition, while no protective effect on high dose C75 addition. In summary, the mtFAS II pathway has a vital role in mitochondrial function. Besides FASN, C75 might also inhibit HsmtKAS, thereby reducing LA production, impairing mitochondrial function, and potentially having toxic effects. LA supplements sufficiently ameliorated the toxicity of C75, showing that a combination of C75 and LA may be a reliable cancer treatment.
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