Li Chunlei, Liu Wenxuan, Liu Youzhao, Wang Weixing, Deng Wenhong
Department of General Surgery, Renmin Hospital of Wuhan University, No.238, Jiefang Road, Wuchang District, Wuhan, 430060, Hubei Province, China.
Hubei Key Laboratory of Digestive System Disease, No.238, Jiefang Road, Wuchang District, Wuhan, 430060, Hubei Province, China.
Sci Rep. 2024 Dec 3;14(1):30043. doi: 10.1038/s41598-024-81448-1.
ATP citrate lyase (ACLY) and acyl-CoA short-chain synthetases 2 (ACSS2) are key enzymes in lipid metabolism. We explored the role of ACLY in gastric cancer (GC) and the effect of ACLY and ACSS2 compensation on GC growth. We used immunohistochemistry to verify the expression level of ACLY in GC, shRNA to stably knock down the expression level of ACLY in GC cells. The expression levels of lipid metabolizing enzymes were verified by qPCR and WB, and targeted lipidomics and quantification of lipid metabolism-related indicators helped us to understand the changes in lipid metabolism. Finally, subcutaneous graft tumors validate our findings from in vitro experiments. ACLY is upregulated in GC tissues, downregulation of ACLY reduced lipid accumulation and inhibited GC proliferation, migration, and invasion in vitro. ACSS2 maintains cell growth by compensatory elevation to maintain fatty acid synthesis activity in ACLY-depleted GC cells. Inhibition of ACSS2 enhanced the inhibitory effect of downregulation of ACLY on the growth of transplanted tumors in nude mice. Downregulation of ACLY inhibited GC cell growth in vitro and in vivo. ACSS2 was compensated to increase to maintain cell growth in ACLY-depleted GC cells.
ATP柠檬酸裂解酶（ACLY）和酰基辅酶A短链合成酶2（ACSS2）是脂质代谢中的关键酶。我们探究了ACLY在胃癌（GC）中的作用以及ACLY和ACSS2补偿对GC生长的影响。我们使用免疫组化来验证ACLY在GC中的表达水平，利用短发夹RNA（shRNA）稳定敲低GC细胞中ACLY的表达水平。通过定量聚合酶链反应（qPCR）和蛋白质免疫印迹法（WB）验证脂质代谢酶的表达水平，靶向脂质组学和脂质代谢相关指标的定量分析帮助我们了解脂质代谢的变化。最后，皮下移植瘤验证了我们体外实验的结果。ACLY在GC组织中上调，ACLY的下调减少了脂质积累，并在体外抑制了GC的增殖、迁移和侵袭。ACSS2通过代偿性升高来维持细胞生长，以保持ACLY缺失的GC细胞中的脂肪酸合成活性。抑制ACSS2增强了ACLY下调对裸鼠移植瘤生长的抑制作用。ACLY的下调在体外和体内均抑制了GC细胞的生长。ACSS2被代偿性上调以维持ACLY缺失的GC细胞的生长。
