典型文献
PGK1-coupled HSP90 stabilizes GSK3β expression to regulate the stemness of breast cancer stem cells
文献摘要：
Objective: Glycogen synthase kinase-3β (GSK3β) has been recognized as a suppressor of Wnt/β-catenin signaling, which is critical for the stemness maintenance of breast cancer stem cells. However, the regulatory mechanisms of GSK3β protein expression remain elusive. Methods: Co-immunoprecipitation and mass spectral assays were performed to identify molecules binding to GSK3β, and to characterize the interactions of GSK3β, heat shock protein 90 (Hsp90), and co-chaperones. The role of PGK1 in Hsp90 chaperoning GSK3β was evaluated by constructing 293T cells stably expressing different domains/mutants of Hsp90α, and by performing a series of binding assays with bacterially purified proteins and clinical specimens. The influences of Hsp90 inhibitors on breast cancer stem cell stemness were investigated by Western blot and mammosphere formation assays. Results: We showed that GSK3β was a client protein of Hsp90. Hsp90, which did not directly bind to GSK3β, interacted with phosphoglycerate kinase 1 via its C-terminal domain, thereby facilitating the binding of GSK3β to Hsp90. GSK3β-bound PGK1 interacted with Hsp90 in the "closed" conformation and stabilized GSK3β expression in an Hsp90 activity-dependent manner. The Hsp90 inhibitor, 17-AAG, rather than HDN-1, disrupted the interaction between Hsp90 and PGK1, and reduced GSK3β expression, resulting in significantly reduced inhibition of β-catenin expression, to maintain the stemness of breast cancer stem cells. Conclusions: Our findings identified a novel regulatory mechanism of GSK3β expression involving metabolic enzyme PGK1- coupled Hsp90, and highlighted the potential for more effective cancer treatment by selecting Hsp90 inhibitors that do not affect PGK1-regulated GSK3β expression.
文献关键词：
中图分类号：
作者姓名：
Wei Tang;Yu Wu;Xin Qi;Rilei Yu;Zhimin Lu;Ao Chen;Xinglong Fan;Jing Li
作者机构：
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China;Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of the First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China;Department of Thoracic Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266003, China;Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266003, China;Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China
文献出处：
引用格式：
[1]Wei Tang;Yu Wu;Xin Qi;Rilei Yu;Zhimin Lu;Ao Chen;Xinglong Fan;Jing Li-.PGK1-coupled HSP90 stabilizes GSK3β expression to regulate the stemness of breast cancer stem cells)[J].癌症生物学与医学（英文版）,2022(04):486-503
A类：
chaperoning,mammosphere
B类：
PGK1,coupled,HSP90,stabilizes,GSK3,expression,stemness,breast,cancer,cells,Objective,Glycogen,synthase,kinase,been,recognized,suppressor,Wnt,catenin,signaling,which,critical,maintenance,However,regulatory,mechanisms,remain,elusive,Methods,immunoprecipitation,mass,spectral,assays,were,performed,identify,molecules,binding,characterize,interactions,heat,shock,Hsp90,chaperones,role,was,evaluated,constructing,293T,stably,expressing,different,domains,mutants,performing,series,bacterially,purified,proteins,clinical,specimens,influences,inhibitors,investigated,blot,Results,showed,that,client,did,not,directly,interacted,phosphoglycerate,via,its,terminal,thereby,facilitating,bound,closed,conformation,stabilized,activity,dependent,manner,AAG,rather,than,HDN,disrupted,between,reduced,resulting,significantly,inhibition,maintain,Conclusions,Our,findings,identified,novel,involving,metabolic,enzyme,highlighted,potential,more,effective,treatment,selecting,affect,regulated
AB值：
0.488053
相似文献
机标中图分类号，由域田数据科技根据网络公开资料自动分析生成，仅供学习研究参考。
