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Upregulation of CPT1A is essential for the tumor-promoting effect of adipocytes in colon cancer.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-09-10 , DOI: 10.1038/s41419-020-02936-6
Xiaopeng Xiong 1 , Yang-An Wen 1 , Rachelle Fairchild 1 , Yekaterina Y Zaytseva 2 , Heidi L Weiss 1 , B Mark Evers 1, 3 , Tianyan Gao 1, 4
Affiliation  

Colon tumors grow in an adipose tissue-enriched microenvironment. Locally advanced colon cancers often invade into surrounding adipose tissue with a direct contact with adipocytes. We have previously shown that adipocytes promote tumor growth by modulating cellular metabolism. Here we demonstrate that carnitine palmitoyltransferase I (CPT1A), a key enzyme controlling fatty acid oxidation (FAO), was upregulated in colon cancer cells upon exposure to adipocytes or fatty acids. In addition, CPT1A expression was increased in invasive tumor cells within the adipose tissue compared to tumors without direct contact with adipocytes. Silencing CPT1A abolished the protective effect provided by fatty acids against nutrient deprivation and reduced tumor organoid formation in 3D culture and the expression of genes associated with cancer stem cells downstream of Wnt/β-catenin. Mechanistically, CPT1A-dependent FAO promoted the acetylation and nuclear translocation of β-catenin. Furthermore, knockdown of CPT1A blocked the tumor-promoting effect of adipocytes in vivo and inhibited xenograft tumor initiation. Taken together, our findings identify CPT1A-depedent FAO as an essential metabolic pathway that enables the interaction between adipocytes and colon cancer cells.



中文翻译:

CPT1A 的上调对于结肠癌中脂肪细胞的促肿瘤作用至关重要。

结肠肿瘤在富含脂肪组织的微环境中生长。局部晚期结肠癌经常侵入周围的脂肪组织并与脂肪细胞直接接触。我们之前已经证明脂肪细胞通过调节细胞代谢来促进肿瘤生长。在这里,我们证明肉碱棕榈酰转移酶 I (CPT1A) 是一种控制脂肪酸氧化 (FAO) 的关键酶,在暴露于脂肪细胞或脂肪酸后,结肠癌细胞中的表达上调。此外,与不直接接触脂肪细胞的肿瘤相比,脂肪组织内的侵袭性肿瘤细胞中的 CPT1A 表达增加。沉默 CPT1A 消除了脂肪酸对营养剥夺的保护作用,并减少了 3D 培养中肿瘤类器官的形成以及与 Wnt/β-catenin 下游癌症干细胞相关的基因的表达。从机制上讲,CPT1A依赖性FAO促进β-连环蛋白的乙酰化和核转位。此外,CPT1A 的敲低可阻断体内脂肪细胞的促肿瘤作用,并抑制异种移植肿瘤的发生。综上所述,我们的研究结果表明 CPT1A 依赖性的 FAO 是一种重要的代谢途径,能够促进脂肪细胞和结肠癌细胞之间的相互作用。

更新日期:2020-09-10
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