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
  • 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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