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川陈皮素通过抑制 GSK3β 抑制胆管癌增殖。

Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β.

机构信息

Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.

Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.

出版信息

Int J Biol Sci. 2022 Sep 11;18(15):5698-5712. doi: 10.7150/ijbs.78345. eCollection 2022.

DOI:10.7150/ijbs.78345
PMID:36263164
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9576508/
Abstract

Cholangiocarcinoma (CCA) is a type of hepatobiliary cancer characterized by uncontrolled cell proliferation, with a poor prognosis and high mortality. Nobiletin (NBT) is a promising anti-tumor compound derived from the peels of oranges and other citrus plants, citrus plant. But the effect of NBT on CCA remains unknown. Our data showed that NBT suppressed CCA cell proliferation and . Colony formation and Edu assay indicated that NBT inhibited cell proliferation. Cell cycle analysis showed that NBT arrested the cell cycle in G0/G1 phase. Target prediction showed that GSK3β was a direct target. Western blot and immunofluorescence confirmed that NBT reduced the phosphorylation of GSK3β. The antiproliferative effect of NBT was intercepted in GSK3β knockdown CCA cells. The cellular thermal shift assay (CETSA) showed NBT directly bound to GSK3β. Finally, NBT showed an anti-proliferative effect in tumor-bearing mice with no hepatotoxicity. NBT could inhibit CCA proliferation, and the pharmacological activity of NBT in CCA was attributed to its direct binding to GSK3β. We suggested that NBT might be a potential natural medicine in CCA treatment.

摘要

胆管癌（CCA）是一种具有不受控制的细胞增殖特征的肝胆癌，预后不良，死亡率高。诺比汀（NBT）是一种有前途的抗肿瘤化合物，来源于橙子和其他柑橘类植物的果皮。但 NBT 对 CCA 的作用尚不清楚。我们的数据显示，NBT 抑制了 CCA 细胞的增殖和集落形成和 Edu 检测表明 NBT 抑制了细胞增殖。细胞周期分析表明，NBT 将细胞周期阻滞在 G0/G1 期。靶标预测表明 GSK3β 是直接靶标。Western blot 和免疫荧光证实 NBT 降低了 GSK3β 的磷酸化。在 GSK3β 敲低的 CCA 细胞中，NBT 的增殖抑制作用被阻断。细胞热转移分析（CETSA）表明 NBT 直接与 GSK3β 结合。最后，NBT 在无肝毒性的荷瘤小鼠中表现出抗增殖作用。NBT 可抑制 CCA 的增殖，NBT 在 CCA 中的药理活性归因于其与 GSK3β 的直接结合。我们建议 NBT 可能是 CCA 治疗的一种潜在天然药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/0d82ae92ba51/ijbsv18p5698g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/932718361200/ijbsv18p5698g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/8a6a16df33a8/ijbsv18p5698g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/449c515c00c0/ijbsv18p5698g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/3e2a4e899239/ijbsv18p5698g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/31a7a209c871/ijbsv18p5698g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/3bd6ae3fb1ad/ijbsv18p5698g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/0420cf5c4061/ijbsv18p5698g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/bff0bf06515e/ijbsv18p5698g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/0d82ae92ba51/ijbsv18p5698g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/932718361200/ijbsv18p5698g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/8a6a16df33a8/ijbsv18p5698g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/449c515c00c0/ijbsv18p5698g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/3e2a4e899239/ijbsv18p5698g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/31a7a209c871/ijbsv18p5698g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/3bd6ae3fb1ad/ijbsv18p5698g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/0420cf5c4061/ijbsv18p5698g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/bff0bf06515e/ijbsv18p5698g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d9c/9576508/0d82ae92ba51/ijbsv18p5698g009.jpg

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