Adaptive antioxidant response to mitochondrial fatty acid oxidation determines the proliferative outcome of cancer cells

• Published in: Cancer letters 2023-02, Vol.554, p.216010-216010, Article 216010
• Main Authors: Castelli, Serena, Ciccarone, Fabio, De Falco, Pamela, Ciriolo, Maria Rosa
• Format: Article
• Language: English
• Subjects: Aerobic glycolysis; Antioxidants; Antioxidants - metabolism; Antioxidants - pharmacology; Fatty Acids - metabolism; Humans; Lipid catabolism; Lipid Metabolism; Lipids; Mitochondrial metabolism; Neoplasms - drug therapy; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species - metabolism; ROS
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.216010

Alterations in lipid catabolism have been broadly described in cancer cells and show tumor-type specific effects on proliferation and cell survival. The factor(s) responsible for this heterogeneity is currently unknown and represents the main limitation in the development of therapeutic interventions that impair lipid metabolism. In this study, we focused on hexanoic acid, a medium-chain fatty acid, that can quickly boost oxidative metabolism by passively crossing mitochondrial membranes. We demonstrated that the antioxidant adaptation of cancer cells to increased fatty acid oxidation is predictive of the proliferative outcome. By interfering with SOD1 expression and glutathione homeostasis, we verified that mitochondrial fatty acid oxidation has antitumor effects in cancer cells that efficiently buffer ROS. In contrast, increased ROS levels promote proliferation in cells with an imbalanced antioxidant response. In addition, an increase in mitochondrial mass and mitophagy activation were observed, respectively. Overall, these data demonstrate that the capacity to manage ROS from mitochondrial oxidative metabolism determines whether lipid catabolism is advantageous or detrimental for cancer cells. •Increasing fatty acid oxidation modulates proliferation in a tumor-dependent manner.•Medium-chain fatty acid imposes different metabolic cell adaptation.•Adaptive antioxidant response to lipid catabolism drives the effect on proliferation.•Modulating antioxidant defences reverts the effects induced by lipid catabolism.