Inhibition of lipid metabolism exerts antitumor effects on rhabdomyosarcoma

Background: and aims: Rhabdomyosarcoma (RMS) exhibits tumor-specific energy metabolic changes that include the Warburg effect. Since targeting cancer metabolism is a promising therapeutic approach, we examined the antitumor effects of suppressing lipid metabolism in RMS. Methods: : We suppressed lipid metabolism in RMS cells in vitro by administering an inhibitor of malonyl-CoA decarboxylase, which increases malonyl CoA and decreases fatty acid oxidation. In vivo studies involved injection of human Rh30 cells into the gastrocnemius muscle of 6-week-old female nude mice, which were divided into two groups: normal chow diet group (NCD) and low-fat diet group (LFD). Results: : Suppression of lipid metabolism in RMS cells decreased cell proliferation by inducing cell cycle arrest. Metabolomic analysis showed an increase in glycolysis and inactivation of the pentose phosphate pathway. Immunoblotting analysis revealed upregulated expression of LC3A/B-II, an autophagy marker, due to increased phosphorylation of AMP-activated protein kinase (AMPK), a nutrient sensor. Inhibition of both lipid metabolism and autophagy suppressed tumor proliferation and increased apoptosis. Moreover, mice fed a LFD for 21-days showed reduced tumor growth compared to NCD-fed mice. Conclusion: Suppression of lipid metabolism disrupted the equilibrium of the cancer-specific metabolism in RMS, resulting in a tumor growth-inhibitory effect. Therefore, the development of treatments focusing on the lipid dependence of RMS is highly promising.