Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.

Abstract

Simple SummaryThe Warburg effect, the utilization of glycolysis as a source of ATP under normoxia, is one of the main hallmarks of cancer. It is included in a wider concept of the metabolic adaptations of cancer cells, in which mitochondria also have crucial roles. Indeed, mitochondria are responsible for the catabolism of macromolecules, which then feeds oxidative phosphorylation. Among the catabolic pathways, fatty acid oxidation is the most efficient in energy supply, but is harmful due to the unavoidable production of reactive oxygen species (ROS). Therefore, the heterogeneity in cancer’s metabolic adaptations is partly due to the capacity to cope with those pro-oxidant compounds. Herein, we will highlight recent results showing the opposite effects of lipid catabolism on cancer progression depending on intracellular ROS. In parallel, we will analyze the evidence of the regulation of lipid catabolism by ROS. Finally, we will summarize the consequences of the mutual relation of fatty acid oxidation and ROS for therapeutic purposes.Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.