Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
Biochim Biophys Acta Mol Basis Dis. 2023 Jun;1869(5):166694. doi: 10.1016/j.bbadis.2023.166694. Epub 2023 Mar 25.
Cholangiocarcinoma (CCA), a cancer of the biliary tract, is a significant health problem in Thailand. Reprogramming of cellular metabolism and upregulation of lipogenic enzymes have been revealed in CCA, but the mechanism is unclear. The current study highlighted the importance of acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme in de novo lipogenesis, on CCA migration. ACC1 expression in human CCA tissues was determined by immunohistochemistry. The results demonstrated that increased ACC1 was related to the shorter survival of CCA patients. Herein, ACC1-deficient cell lines (ACC1-KD) were generated by the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (cas9) system and were used for the comparative study. The ACC1 levels in ACC1-KD were 80-90 % lower than in parental cells. Suppression of ACC1 significantly reduced intracellular malonyl-CoA and neutral lipid contents. Two-fold growth retardation and 60-80 % reduced CCA cell migration and invasion were observed in ACC1-KD cells. The reduced 20-40 % of intracellular ATP levels, AMPK activation, lowered NF-κB p65 nuclear translocation, and snail expression were emphasized. Migration of ACC1-KD cells was restored by supplementation with palmitic acid and malonyl-CoA. Altogether, the importance of rate-limiting enzyme in de novo fatty acid synthesis, ACC1, and AMPK-NF-κB-snail axis on CCA progression was suggested herein. These might be the novel targets for CCA drug design. (ACC1, AMPK, Cholangiocarcinoma, De novo lipogenesis, NF-κB, Palmitic acid).
胆管癌（CCA）是一种胆道癌症，在泰国是一个严重的健康问题。在 CCA 中已经揭示了细胞代谢的重新编程和脂肪生成酶的上调，但机制尚不清楚。本研究强调了乙酰辅酶 A 羧化酶 1（ACC1）在 CCA 迁移中的重要性，ACC1 是从头合成脂肪的限速酶。通过免疫组织化学测定人 CCA 组织中的 ACC1 表达。结果表明，ACC1 的增加与 CCA 患者的生存时间缩短有关。在此，通过簇状规则间隔短回文重复（CRISPR）-CRISPR 相关蛋白 9（cas9）系统生成了 ACC1 缺陷细胞系（ACC1-KD），并用于比较研究。ACC1-KD 中的 ACC1 水平比亲本细胞低 80-90%。ACC1 的抑制显著降低了细胞内丙二酰 CoA 和中性脂质含量。在 ACC1-KD 细胞中观察到两倍的生长迟缓以及 60-80%的 CCA 细胞迁移和侵袭减少。强调了降低的 20-40%的细胞内 ATP 水平、AMPK 激活、降低的 NF-κB p65 核易位和 snail 表达。通过补充棕榈酸和丙二酰 CoA 恢复了 ACC1-KD 细胞的迁移。总之，本文提出了从头脂肪酸合成的限速酶 ACC1 和 AMPK-NF-κB-snail 轴在 CCA 进展中的重要性。这些可能是 CCA 药物设计的新靶点。（ACC1、AMPK、胆管癌、从头脂肪生成、NF-κB、棕榈酸）。
