Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation Blockage
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, abrogate...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407519 |
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| author | Xiaojing Du Zhuoran Qi Sinuo Chen Jinlan Wu Ye Xu Sunkuan Hu Zhijie Yu Jiayun Hou Yuan Fang Jinglin Xia Xin Cao |
| author_facet | Xiaojing Du Zhuoran Qi Sinuo Chen Jinlan Wu Ye Xu Sunkuan Hu Zhijie Yu Jiayun Hou Yuan Fang Jinglin Xia Xin Cao |
| author_sort | Xiaojing Du |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-da4b280952784a989ccd9588af21983d |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-da4b280952784a989ccd9588af21983d2025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202407519Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation BlockageXiaojing Du0Zhuoran Qi1Sinuo Chen2Jinlan Wu3Ye Xu4Sunkuan Hu5Zhijie Yu6Jiayun Hou7Yuan Fang8Jinglin Xia9Xin Cao10Liver Cancer Institute Zhongshan Hospital Fudan University 180 Fenglin Road Shanghai 200032 ChinaLiver Cancer Institute Zhongshan Hospital Fudan University 180 Fenglin Road Shanghai 200032 ChinaLiver Cancer Institute Zhongshan Hospital Fudan University 180 Fenglin Road Shanghai 200032 ChinaDepartment of Pediatrics Jiading District Central Hospital Shanghai 201800 ChinaLiver Cancer Institute Zhongshan Hospital Fudan University 180 Fenglin Road Shanghai 200032 ChinaDepartment of Gastroenterology The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Diagnosis and Treatment of Severe Hepato‐Pancreatic Diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000 ChinaBiomedical Research Center Zhongshan Hospital Institute of Clinical Science Fudan University Shanghai 200032 ChinaDepartment of Liver Surgery Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education) Liver Cancer Institute Zhongshan Hospital Fudan University Shanghai 200032 ChinaLiver Cancer Institute Zhongshan Hospital Fudan University 180 Fenglin Road Shanghai 200032 ChinaInstitute of Clinical Science Zhongshan Hospital Fudan University Shanghai 200032 ChinaAbstract 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.https://doi.org/10.1002/advs.202407519core fucosylationcytoskeletonintrahepatic cholangiocarcinomaP‐selectin/PSGL1synthetic retinoidtumor‐repopulating cells |
| spellingShingle | Xiaojing Du Zhuoran Qi Sinuo Chen Jinlan Wu Ye Xu Sunkuan Hu Zhijie Yu Jiayun Hou Yuan Fang Jinglin Xia Xin Cao Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation Blockage Advanced Science core fucosylation cytoskeleton intrahepatic cholangiocarcinoma P‐selectin/PSGL1 synthetic retinoid tumor‐repopulating cells |
| title | Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation Blockage |
| title_full | Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation Blockage |
| title_fullStr | Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation Blockage |
| title_full_unstemmed | Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation Blockage |
| title_short | Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor‐Repopulating Cells of Intrahepatic Cholangiocarcinoma via Disrupting Cytoskeleton by P‐Selectin/PSGL1 N‐Glycosylation Blockage |
| title_sort | synthetic retinoid sulfarotene selectively inhibits tumor repopulating cells of intrahepatic cholangiocarcinoma via disrupting cytoskeleton by p selectin psgl1 n glycosylation blockage |
| topic | core fucosylation cytoskeleton intrahepatic cholangiocarcinoma P‐selectin/PSGL1 synthetic retinoid tumor‐repopulating cells |
| url | https://doi.org/10.1002/advs.202407519 |
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