羧胺三唑乳清酸盐对人胰腺癌细胞系增殖及脂肪酸合成代谢的影响  

Effect of carboxyamidotriazole-orotate on proliferation and fatty acid anabolism of human pancreatic cancer cell lines

作　　者：郭泓江 徐也婷 张迪雅 仇佳星 王钰铖 鞠瑞[1] 郭磊[1] GUO Hongjiang;XU Yeting;ZHANG Diya;QIU Jiaxing;WANG Yucheng;JU Rui;GUO Lei(Department of Pharmacology,Institute of Basic Medical Sciences CAMS,School of Basic Medicine PUMC,Beijing 100005,China)

机构地区：[1]中国医学科学院基础医学研究所、北京协和医学院基础学院药理学系,北京100005

出　　处：《基础医学与临床》2024年第4期440-446,共7页Basic and Clinical Medicine

基　　金：国家自然科学基金(82002094);中国医学科学院医学与健康科技创新工程(2022-I2M-2-002);北京市自然科学基金(7222254)。

摘　　要：目的 研究羧胺三唑乳清酸盐(CTO)对人胰腺癌细胞增殖影响及对其脂肪酸合成代谢的调控作用。方法 以人胰腺癌细胞系AsPC-1、AsPC-1/GEM(简称AR)、PANC-1、MiaPaCa-2为研究对象,用磺酰罗丹明B(SRB)检测细胞存活率,采用qPCR检测胰腺癌细胞系中脂肪酸合成关键基因mRNA水平,用Western blot检测细胞内腺苷单磷酸依赖蛋白激酶(AMPK)和乙酰辅酶A羧化酶(ACC)通路蛋白表达;利用液相色谱-质谱联用代谢组学技术检测细胞内脂质代谢物质差异。结果 与对照组相比,CTO显著降低AsPC-1、AR、PANC-1、MiaPaCa-2 4株人胰腺癌细胞活率(P<0.05);CTO下调细胞内脂肪酸合成关键基因的mRNA水平(P<0.05);CTO下调细胞中AMPK、ACC及c-Myc蛋白表达(P<0.05),而增加p-AMPK、p-ACC蛋白表达(P<0.05);CTO减少AR细胞中脂质代谢物含量(P<0.05)。结论 CTO通过抑制癌基因c-Myc蛋白表达及AMPK/ACC通路,下调脂肪酸合成相关基因的表达活性,减弱细胞脂肪酸合成代谢能力,进而抑制人胰腺癌细胞系AsPC-1、AR、PANC-1、MiaPaCa-2的增殖能力。Objective To study the effect of carboxyamidotriazole-orotate(CTO)on the proliferation and fatty acid anabolism regulation of human pancreatic cancer cells.Methods Human pancreatic cancer cell lines AsPC-1,AsPC-1/GEM(AR),PANC-1 and MiaPaCa-2 were used as the study subjects;cell survival rate was detected by sulfonylrhodamine B(SRB);the mRNA level of key genes for fatty acid synthesis was detected by qPCR;the protein level of the AMPK/ACC pathway was detected by Western blot;intracellular lipid metabolites were examined by liquid chromatography-mass spectrometry(LC-MS).Results Comparing to control group,CTO significantly decreased the cell viability of AsPC-1,AR,PANC-1,and MiaPaCa-2(P<0.05).CTO down-regulated the mRNA level of key fatty acid synthesis genes(P<0.05).CTO significantly reduced the protein expression of AMPK,ACC and c-Myc(P<0.05),while increasing the protein expression of p-AMPK and p-ACC(P<0.05).CTO decreased lipid metabolite content in AR cells(P<0.05).Conclusions CTO attenuates cellular fatty acid anabolism by inhibition of oncogene c-Myc expression and AMPK/ACC pathway,down-regulates the expression of fatty acid synthesis-related genes,and then inhibits proliferation of the human pancreatic cancer cell lines AsPC-1,AR,PANC-1 and MiaPaCa-2.

关 键 词：羧胺三唑乳清酸盐 胰腺癌 增殖 脂肪酸合成代谢 

分 类 号：R96[医药卫生—药理学]