2. Academic Validation
  3. Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor-Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P-Selectin/PSGL1 N-Glycosylation Blockage

Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor-Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P-Selectin/PSGL1 N-Glycosylation Blockage

  • Adv Sci (Weinh). 2025 Jan;12(3):e2407519. doi: 10.1002/advs.202407519.
Xiaojing Du 1 2,  Zhuoran Qi 1,  Sinuo Chen 1,  Jinlan Wu 3,  Ye Xu 1,  Sunkuan Hu 4,  Zhijie Yu 5 6,  Jiayun Hou 7,  Yuan Fang 8,  Jinglin Xia 1 9,  Xin Cao 10
Affiliations

Affiliations

  • 1 Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
  • 2 Endoscopy Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
  • 3 Department of Pediatrics, Jiading District Central Hospital, Shanghai, 201800, China.
  • 4 Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 5 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 6 Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 7 Biomedical Research Center, Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai, 200032, China.
  • 8 Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 9 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 10 Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
PMID: 39605300 DOI: 10.1002/advs.202407519
Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly lethal malignancy that currently lacks effective clinical treatments. Eliminating stem cell-like Cancer cells is an extremely promising but challenging strategy for treating ICC. A recently developed synthetic retinoid, sulfarotene, abrogates proliferation, and induces Apoptosis of tumor-repopulating cells (TRCs) that exhibit stem cell-like properties, yet its effect and underlying mechanisms remain elusive in ICC. It is found that although 5-fluorouracil, cisplatin, pemigatinib, and gemcitabine all inhibit ICC-TRCs, sulfarotene demonstrates superior efficacy. Sulfarotene induces retinoic acid receptor alpha (RARɑ) translocation from the cytoplasm to the nucleus, suppressing P-selectin expression at the transcriptional level. Moreover, it directly interacts with fucosyltransferase 8 (FUT8), inhibiting the core fucosylation of P-selectin glycoprotein ligand 1 (PSGL1). These actions collectively inhibit ICC-TRCs via destroying PSGL1-regulated Cytoskeleton. The findings provide a strategy of inhibiting P-selectin/PSGL1 interaction and altering PSGL1 glycosylation pattern to compromise the cytoskeletal integrity and eliminate ICC-TRCs.

Keywords

P‐selectin/PSGL1; core fucosylation; cytoskeleton; intrahepatic cholangiocarcinoma; synthetic retinoid; tumor‐repopulating cells.

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