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IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation

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 th...

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Autores principales: Feng, Tingting, Wang, Jing, Cheng, Kai, Lu, Qiqi, Zhao, Ru, Wang, Shiguan, Zhang, Qingyun, Ge, Luna, Pan, Jihong, Song, Guanhua, Wang, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Compuscript 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334759/
https://www.ncbi.nlm.nih.gov/pubmed/34652890
http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0583
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author Feng, Tingting
Wang, Jing
Cheng, Kai
Lu, Qiqi
Zhao, Ru
Wang, Shiguan
Zhang, Qingyun
Ge, Luna
Pan, Jihong
Song, Guanhua
Wang, Lin
author_facet Feng, Tingting
Wang, Jing
Cheng, Kai
Lu, Qiqi
Zhao, Ru
Wang, Shiguan
Zhang, Qingyun
Ge, Luna
Pan, Jihong
Song, Guanhua
Wang, Lin
author_sort Feng, Tingting
collection PubMed
description 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.
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spelling pubmed-93347592022-08-09 IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation Feng, Tingting Wang, Jing Cheng, Kai Lu, Qiqi Zhao, Ru Wang, Shiguan Zhang, Qingyun Ge, Luna Pan, Jihong Song, Guanhua Wang, Lin Cancer Biol Med Original Article 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. Compuscript 2022-07-15 2021-10-18 /pmc/articles/PMC9334759/ /pubmed/34652890 http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0583 Text en Copyright: © 2022, Cancer Biology & Medicine https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0 (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
spellingShingle Original Article
Feng, Tingting
Wang, Jing
Cheng, Kai
Lu, Qiqi
Zhao, Ru
Wang, Shiguan
Zhang, Qingyun
Ge, Luna
Pan, Jihong
Song, Guanhua
Wang, Lin
IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation
title IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation
title_full IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation
title_fullStr IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation
title_full_unstemmed IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation
title_short IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation
title_sort il13rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334759/
https://www.ncbi.nlm.nih.gov/pubmed/34652890
http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0583
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