Abstract
Rhabdomyosarcoma 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 rhabdomyosarcoma. We suppressed lipid metabolism in rhabdomyosarcoma cells in vitro by administering an inhibitor of malonyl‐CoA decarboxylase, which increases malonyl‐CoA and decreases fatty acid oxidation. Suppression of lipid metabolism in rhabdomyosarcoma 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 the autophagy marker LC3A/B‐II due to increased phosphorylation of AMP‐activated protein kinase, a nutrient sensor. p21 protein expression level also increased. Inhibition of both lipid metabolism and autophagy suppressed tumor proliferation and increased apoptosis. In vivo studies involved injection of human Rh30 cells into the gastrocnemius muscle of 6‐week‐old female nude mice, which were divided into normal chow and low‐fat diet groups. The mice fed a low‐fat diet for 21 days showed reduced tumor growth compared to normal chow diet‐fed mice. Suppression of lipid metabolism disrupted the equilibrium of the cancer‐specific metabolism in rhabdomyosarcoma, resulting in a tumor growth‐inhibition effect. Therefore, the development of treatments focusing on the lipid dependence of rhabdomyosarcoma is highly promising.
Highlights
Rhabdomyosarcoma (RMS), the most prevalent malignancy among pediatric soft tissue tumors [1,2,3], arises from myogenic mesenchymal progenitors and occurs in various parts and tissues of the body, such as the bladder, gonads, nasopharyngeal cavity, paranasal sinuses, parameninges, orbit, and skeletal muscle [4, 5]
Suppression of lipid metabolism disrupted the equilibrium of the cancer-specific metabolism in RMS, resulting in a tumor growth-inhibitory effect
Pkm1 derived pyruvate is preferentially destined for the mitochondrial tricarboxylic acid (TCA) cycle, while Pkm2 derived pyruvate is predominantly destined for lactate production
Summary
Rhabdomyosarcoma (RMS), the most prevalent malignancy among pediatric soft tissue tumors [1,2,3], arises from myogenic mesenchymal progenitors and occurs in various parts and tissues of the body, such as the bladder, gonads, nasopharyngeal cavity, paranasal sinuses, parameninges, orbit, and skeletal muscle [4, 5]. Cancer cells synthesize adenosine triphosphate (ATP) primarily via glycolysis in the cytoplasm, which does not require oxygen, rather than oxidative phosphorylation in mitochondria, even in an oxygen-rich environment. This phenomenon was first proposed by Otto Warburg approximately 100 years ago, and later named as the Warburg effect or ‘aerobic glycolysis’ [6, 7]. It has been reported that glycolysis is significantly upregulated in Rh30, an alveolar-type RMS cell line, compared with normal myocytes [10]. 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
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