Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Pediatrics, Uji Takeda Hospital, Kyoto, Japan.
Cancer Med. 2021 Sep;10(18):6442-6455. doi: 10.1002/cam4.4185. Epub 2021 Sep 2.
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.
横纹肌肉瘤表现出肿瘤特异性的能量代谢变化，包括瓦博格效应。由于靶向肿瘤代谢是一种很有前途的治疗方法，我们研究了抑制横纹肌肉瘤中脂质代谢的抗肿瘤作用。我们通过给予丙二酰辅酶 A 脱羧酶抑制剂来抑制横纹肌肉瘤细胞中的脂质代谢，从而增加丙二酰辅酶 A 并减少脂肪酸氧化。抑制横纹肌肉瘤细胞中的脂质代谢通过诱导细胞周期停滞来减少细胞增殖。代谢组学分析显示糖酵解增加和戊糖磷酸途径失活。免疫印迹分析显示由于 AMP 激活的蛋白激酶（一种营养传感器）的磷酸化增加，自噬标志物 LC3A/B-II 的表达上调。p21 蛋白表达水平也增加。同时抑制脂质代谢和自噬抑制肿瘤增殖并增加细胞凋亡。体内研究涉及将人 Rh30 细胞注射到 6 周龄雌性裸鼠的腓肠肌中，将它们分为正常饲料组和低脂饮食组。与正常饲料喂养的小鼠相比，低脂饮食喂养 21 天的小鼠肿瘤生长减少。抑制脂质代谢破坏了横纹肌肉瘤中癌症特异性代谢的平衡，从而产生肿瘤生长抑制作用。因此，开发针对横纹肌肉瘤脂质依赖性的治疗方法具有很高的前景。
