Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040, China; Shanghai Institute of Geriatrics and Gerontology, Shanghai 200040, China; Department of Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Cell Rep. 2024 Oct 22;43(10):114818. doi: 10.1016/j.celrep.2024.114818. Epub 2024 Oct 9.
Selective serotonin reuptake inhibitors (SSRIs) have shown promise in cancer therapy, particularly for hepatocellular carcinoma (HCC), but their molecular targets and mechanisms remain unclear. Here, we show that SSRIs exhibit significant anti-HCC effects independent of their classical target, the serotonin reuptake transporter (SERT). Using global inverse gene expression profiling, drug affinity responsive target stability assays, and in silico molecular docking, we demonstrate that citalopram targets glucose transporter 1 (GLUT1), resulting in reduced glycolytic flux. A mutant GLUT1 variant at the citalopram binding site (E380) diminishes the drug's inhibitory effects on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth of GLUT1 liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis reveals that SSRI use correlates with a lower risk of metastasis among patients with HCC. Our study describes a role for SSRIs in cancer metabolism, establishing a rationale for their repurposing as potential anti-cancer drugs for HCC.
选择性 5-羟色胺再摄取抑制剂（SSRIs）在癌症治疗中显示出了希望，特别是对肝细胞癌（HCC），但其分子靶点和机制仍不清楚。在这里，我们表明 SSRIs 具有显著的抗 HCC 作用，而不依赖于其经典靶标，即 5-羟色胺再摄取转运体（SERT）。通过全基因组反基因表达谱分析、药物亲和反应靶标稳定性测定和计算机分子对接，我们证明西酞普兰以葡萄糖转运蛋白 1（GLUT1）为靶点，导致糖酵解通量减少。西酞普兰结合位点（E380）处的 GLUT1 突变体降低了药物对瓦伯格效应和肿瘤生长的抑制作用。在临床前模型中，西酞普兰抑制 GLUT1 肝肿瘤的生长，并与抗 PD-1 治疗具有协同作用。回顾性分析显示，SSRIs 的使用与 HCC 患者转移风险降低相关。我们的研究描述了 SSRIs 在癌症代谢中的作用，为将其重新用作 HCC 的潜在抗癌药物提供了依据。
