Objective: Androgen deprivation therapy (ADT) is still the principal treatment option for prostate cancer (PCa). In addition to reactivation of androgen receptor signaling, the resistance of PCa to apoptosis during ADT also contributes to castration resistant PCa (CRPC). A previous study reported that gene transfer of IL-13Rα2 into PCa cells sensitized the cells to the IL-13R-targeted cytotoxin IL13Rα1, leading to apoptosis. Compared with IL-13Rα2, IL13Rα1 is more constitutively expressed in PCa cells, but its function in PCa remains to be established.Methods: We determined the role and expression of IL13Rα1 in PCa cancer cells using western blotting, flow cytometry, and cell proliferation assays. Co-immunoprecipitation and mass spectrometry were used to identify the proteins that interacted with IL13Rα1, to elucidate its function. Results: In this study, we showed that IL13Rα1 was selectively suppressed in androgen-deprived PCa cells and that its suppression tended to be associated with poor prognoses of PCa patients. IL13Rα1 overexpression promoted apoptosis and inhibited tumor growth under androgen-deprived or castrated conditions (P < 0.01). Mechanistically, IL13Rα1 recruited and facilitated ubiquitin protein ligase E3C-mediated ubiquitination and degradation of hexokinase 2 (HK2), resulting in glycolytic inhibition and eventually leading to PCa cell apoptosis. Furthermore, our data revealed that mutated ataxia-telangiectasia kinase phosphorylated and facilitated the selective ubiquitin proteasome-mediated degradation of HK2. Notably, IL13Rα1-overexpressing PCa cells were more susceptible to apoptosis and exhibited reduced tumor growth after exposure to the HK2 inhibitor, 2-deoxy-D-glucose (P < 0.01). Conclusions: Our data identified a tumor suppressor role for IL13Rα1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis. IL13Rα1-mediated signaling involving HK2 may therefore provide a novel treatment target and strategy for CRPC.

Tingting Feng;Jing Wang;Kai Cheng;Qiqi Lu;Ru Zhao;Shiguan Wang;Qingyun Zhang;Luna Ge;Jihong Pan;Guanhua Song;Lin Wang

Department of Pathology,School of Basic Medical Sciences,Shandong University,Jinan 250012,China;Department of Pathology,The Fourth People's Hospital of Jinan,Jinan 250031,China;Department of PET-CT,Shandong Cancer Hospital and Institute,Shandong First Medical University and Shandong Academy of Medical Sciences,Jinan 250002,China;The Second Hospital,Cheeloo College of Medicine,Shandong University Medical School,Jinan 250012,China;Biomedical Sciences College&Shandong Medicinal Biotechnology Centre,Key Lab for Biotech-Drugs of National Health Commission,Key Lab for Rare&Uncommon Diseases of Shandong Province,Shandong First Medical University&Shandong Academy of Medical Sciences,Jinan 250002,China;Department of Biochemistry and Molecular Biology,Shandong University School of Basic Medical Sciences,Jinan 250012,China;Institute of Basic Medicine,Shandong Academy of Medical Sciences,Shandong First Medical University&Shandong Academy of Medical Sciences,Jinan 250002,China;Department of Oncology,The First Affiliated Hospital of Shandong First Medical University,Jinan 250014,China

癌症生物学与医学（英文版）

[1]Tingting Feng;Jing Wang;Kai Cheng;Qiqi Lu;Ru Zhao;Shiguan Wang;Qingyun Zhang;Luna Ge;Jihong Pan;Guanhua Song;Lin Wang-.IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation)[J].癌症生物学与医学（英文版）,2022(07):1008-1028

IL13R,13R,castrated,E3C

prevents,castration,resistant,phenotype,prostate,cancer,by,targeting,hexokinase,mediated,degradation,Objective,Androgen,deprivation,therapy,ADT,still,principal,treatment,option,PCa,In,addition,reactivation,androgen,receptor,signaling,resistance,apoptosis,during,also,contributes,CRPC,previous,study,reported,that,gene,transfer,into,cells,sensitized,targeted,cytotoxin,leading,Compared,constitutively,expressed,its,function,remains,be,established,Methods,We,determined,role,using,western,blotting,flow,cytometry,proliferation,assays,immunoprecipitation,mass,spectrometry,were,used,identify,proteins,interacted,elucidate,Results,this,showed,was,selectively,suppressed,deprived,suppression,tended,associated,poor,prognoses,patients,overexpression,promoted,inhibited,tumor,growth,under,conditions,Mechanistically,recruited,facilitated,ligase,ubiquitination,HK2,resulting,glycolytic,inhibition,eventually,Furthermore,our,data,revealed,mutated,ataxia,telangiectasia,phosphorylated,proteasome,Notably,overexpressing,susceptible,exhibited,reduced,after,exposure,inhibitor,deoxy,glucose,Conclusions,Our,identified,suppressor,preventing,inhibiting,glycolysis,involving,may,therefore,provide,novel,strategy

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