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 that gene transfer of IL -13R alpha 2 into PCa cells sensitized the cells to the IL-13R- targeted cytotoxin IL13R alpha 1, leading to apoptosis. Compared with IL-13R alpha 2, IL13R alpha 1 is more constitutively expressed in PCa cells, but its function in PCa remains to be established. Methods: We determined the role and expression of IL13R alpha 1 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 IL13R alpha 1, to elucidate its function. Results: In this study, we showed that IL13R alpha 1 was selectively suppressed in androgen-deprived PCa cells and that its suppression tended to be associated with poor prognoses of PCa patients. IL13R alpha 1 overexpression promoted apoptosis and inhibited tumor growth under androgen deprived or castrated conditions (P < 0.01). Mechanistically, IL13R alpha 1 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, IL13R alpha 1-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 IL13R alpha 1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis. IL13R alpha 1-mediated signaling involving HK2 may therefore provide a novel treatment target and strategy for CRPC.

Automated summary

This study identified a tumor suppressor role for IL13R alpha 1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis. IL13R alpha 1-mediated signaling involving HK2 may provide a novel treatment target and strategy for CRPC.