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Post-translational modification of CDK1–STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties

التفاصيل البيبلوغرافية
العنوان: Post-translational modification of CDK1–STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties
المؤلفون: Xiaodong Xu, Yimin Ding, Junbin Jin, Chengjie Xu, Wenyi Hu, Songtao Wu, Guoping Ding, Rui Cheng, Liping Cao, Shengnan Jia
المصدر: Cell & Bioscience, Vol 13, Iss 1, Pp 1-21 (2023)
بيانات النشر: BMC, 2023.
سنة النشر: 2023
المجموعة: LCC:Biotechnology
LCC:Biology (General)
LCC:Biochemistry
مصطلحات موضوعية: CDK1, Fisetin, Cancer stem cells, STAT3, Pancreatic ductal adenocarcinoma, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5, Biochemistry, QD415-436
الوصف: Abstract Background Pancreatic cancer stem cells (CSCs) promote pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and chemoresistance. Cyclin-dependent kinase 1 (CDK1) plays an important role in tumor initiation in other tumors, but the function of CDK1 in PDAC remains unclear. Fisetin is a bioactive flavonoid with anti-tumor properties in multiple tumors, while its function in CSCs remains elusive. Results In this study, we demonstrated that CDK1 was correlated with prognosis and was highly expressed in pancreatic cancer tissue and gemcitabine-resistant cells. Silencing CDK1 impaired tumor stemness and reduced a subset of CSCs. We found that fisetin blocked the kinase pocket domain of CDK1 and inhibited pancreatic CSC characteristics. Using acetylation proteomics analysis and phosphorylation array assay, we confirmed that fisetin reduced CDK1 expression and increased CDK1 acetylation at lysine 33 (K33), which resulted in the suppression of CDK1 phosphorylation. Silencing CDK1 or STAT3 suppressed tumor stemness properties, while overexpressing CDK1 or STAT3 showed the opposite effect. Mutation or acetylation of CDK1 at K33 weakened STAT3 phosphorylation at Y705, impairing the expression of stem-related genes and pancreatic cancer stemness. In addition, lack of histone deacetylase 3 (HDAC3), which deacetylates CDK1, contributed to weakening STAT3 phosphorylation by regulating the post-translational modification of CDK1, thereby decreasing the stemness of PDAC. Moreover, our results revealed that fisetin enhanced the effect of gemcitabine through eliminating a subpopulation of pancreatic CSCs by inhibiting the CDK1–STAT3 axis in vitro and in vivo. Conclusion Our findings highlight the role of post-translational modifications of CDK1–STAT3 signaling in maintaining cancer stemness of PDAC, and indicated that targeting the CDK1–STAT3 axis with inhibitors such as fisetin is a potential therapeutic strategy to diminish drug resistance and eliminate PDAC.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2045-3701
Relation: https://doaj.org/toc/2045-3701
DOI: 10.1186/s13578-023-01118-z
URL الوصول: https://doaj.org/article/21c85a3588504829a20b464c22e33f8a
رقم الأكسشن: edsdoj.21c85a3588504829a20b464c22e33f8a
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:20453701
DOI:10.1186/s13578-023-01118-z