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...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.展开更多
Background:Interleukin 13 receptor subunit alpha 2(IL13RA2)plays an essential role in the progression of many cancers.However,the role of IL13RA2 in infantile haemangioma(IH)is still unknown.Materials and Methods:IL13...Background:Interleukin 13 receptor subunit alpha 2(IL13RA2)plays an essential role in the progression of many cancers.However,the role of IL13RA2 in infantile haemangioma(IH)is still unknown.Materials and Methods:IL13RA2 expression in IH tissues was analyzed using western blot,qRT-PCR,and immunofluorescence.The role of IL13RA2 in haemangioma-derived endothelial cells(HemECs)was determined following knockdown or overexpression of IL13RA2 using CCK-8,colony formation,apoptosis,wound healing,tubule formation,Transwell,and western blot.Results:IL13RA2 expression was upregulated in IH tissues.IL13RA2 overexpression promoted proliferation,migration,and invasion of HemECs and induced glycolysis,which was confirmed with a glycolysis inhibitor.Specifically,IL13RA2 interacted withβ-catenin and activated the Wnt/β-catenin pathway in HemECs,which were involved in the above-mentioned effects of IL13RA2.Conclusions:These findings revealed that targeting IL13RA2 is a potential therapeutic approach for IH.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.81772760 and 82072850)the Natural Science Foundation of Shandong Province(Grant Nos.ZR2020YQ55 and ZR2020QH327),the Shandong Taishan Scholarship(Grant No.tsqn20161076)+1 种基金the Innovation Project of Shandong Academy of Medical Sciences(2020)the program for Outstanding PhD candidate of Shandong University(2020)and Academic promotion programme of Shandong First Medical University(LJ001).
文摘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.
文摘Background:Interleukin 13 receptor subunit alpha 2(IL13RA2)plays an essential role in the progression of many cancers.However,the role of IL13RA2 in infantile haemangioma(IH)is still unknown.Materials and Methods:IL13RA2 expression in IH tissues was analyzed using western blot,qRT-PCR,and immunofluorescence.The role of IL13RA2 in haemangioma-derived endothelial cells(HemECs)was determined following knockdown or overexpression of IL13RA2 using CCK-8,colony formation,apoptosis,wound healing,tubule formation,Transwell,and western blot.Results:IL13RA2 expression was upregulated in IH tissues.IL13RA2 overexpression promoted proliferation,migration,and invasion of HemECs and induced glycolysis,which was confirmed with a glycolysis inhibitor.Specifically,IL13RA2 interacted withβ-catenin and activated the Wnt/β-catenin pathway in HemECs,which were involved in the above-mentioned effects of IL13RA2.Conclusions:These findings revealed that targeting IL13RA2 is a potential therapeutic approach for IH.
