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SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1

Dong, Fangyuan ; He, Kang ; Zhang, Shan ; Song, Kaiyuan ; Jiang, Luju ; Hu, Li-Peng ; Li, Qing ; Zhang, Xue-Li ; Zhang, Naiqi LU orcid and Li, Bo-Tai , et al. (2024) In Cell Reports 43(10).
Abstract

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,... (More)

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
high 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Reports
volume
43
issue
10
article number
114818
publisher
Cell Press
external identifiers
  • scopus:85207330222
  • pmid:39388353
ISSN
2211-1247
DOI
10.1016/j.celrep.2024.114818
language
English
LU publication?
yes
additional info
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
id
49e23189-fe39-4dba-86bc-d86c69556746
date added to LUP
2024-10-14 09:01:31
date last changed
2025-07-05 12:23:10
@article{49e23189-fe39-4dba-86bc-d86c69556746,
  abstract     = {{<p>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<br>
 high 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.<br>
 </p>}},
  author       = {{Dong, Fangyuan and He, Kang and Zhang, Shan and Song, Kaiyuan and Jiang, Luju and Hu, Li-Peng and Li, Qing and Zhang, Xue-Li and Zhang, Naiqi and Li, Bo-Tai and Zhu, Li-Li and Li, Jun and Feng, Mingxuan and Gao, Yunchen and Chen, Jie and Hu, Xiaona and Wang, Jiaofeng and Jiang, Chongyi and Wang, Cun and Zhu, Helen He and Da, Lin-Tai and Ji, Jianguang and Zhang, Zhi-Gang and Bao, Zhijun and Jiang, Shu-Heng}},
  issn         = {{2211-1247}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{10}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2024.114818}},
  doi          = {{10.1016/j.celrep.2024.114818}},
  volume       = {{43}},
  year         = {{2024}},
}