Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai 200092, China.
Department of Gastrointestinal Surgical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fujian, Fuzhou 350014, China.
Biochem Pharmacol. 2022 Nov;205:115253. doi: 10.1016/j.bcp.2022.115253. Epub 2022 Sep 19.
Lithocholic acid (LCA), one of the most common metabolic products of bile acids (BAs), is originally synthesized in the liver, stored in the gallbladder, and released to the intestine, where it assists absorption of lipid-soluble nutrients. LCA has recently emerged as a powerful reagent to inhibit tumorigenesis; however, the anti-tumor activity and molecular mechanisms of LCA in gallbladder cancer (GBC) remain poorly acknowledged. Here, we analyzed serum levels of LCA in human GBC and found that LCA was significantly downregulated in these patients, and reduced LCA levels were associated with poor clinical outcomes. Treatment of xenografts with LCA impeded tumor growth. Furthermore, LCA treatment in GBC cell lines decreased glutaminase (GLS) expression, glutamine (Gln) consumption, and GSH/GSSG and NADPH/NADP ratios, leading to cellular ferroptosis. In contrast, GLS overexpression in tumor cells fully restored GBC proliferation and decreased ROS imbalance, thus suppressing ferroptosis. Our findings reveal that LCA functions as a tumor-suppressive factor in GBC by downregulating GLS-mediated glutamine metabolism and subsequently inducing ferroptosis. This study may offer a new therapeutic strategy tailored to improve the treatment of GBC.
胆酸（LCA）是胆汁酸（BAs）的最常见代谢产物之一，最初在肝脏中合成，储存在胆囊中，并释放到肠道中，以帮助吸收脂溶性营养素。LCA 最近已成为抑制肿瘤发生的有力试剂；然而，LCA 在胆囊癌（GBC）中的抗肿瘤活性和分子机制仍知之甚少。在这里，我们分析了人 GBC 血清中 LCA 的水平，发现 LCA 在这些患者中显著下调，并且降低的 LCA 水平与不良的临床结果相关。用 LCA 处理异种移植物可阻止肿瘤生长。此外，LCA 处理 GBC 细胞系降低了谷氨酰胺酶（GLS）的表达、谷氨酰胺（Gln）的消耗以及 GSH/GSSG 和 NADPH/NADP 比，导致细胞发生铁死亡。相比之下，肿瘤细胞中 GLS 的过表达完全恢复了 GBC 的增殖并减少了 ROS 失衡，从而抑制了铁死亡。我们的研究结果表明，LCA 通过下调 GLS 介导的谷氨酰胺代谢并随后诱导铁死亡，在 GBC 中发挥肿瘤抑制因子的作用。这项研究可能为改善 GBC 的治疗提供一种新的靶向治疗策略。
