Abstract
BackgroundExpression of aberrant cyclin G2 is a key factor contributing to cancer biological processes, including glioma. However, the potential underlying mechanisms of cyclin G2 in the glioma tumor immune microenvironment remain unclear.MethodsCo-immunoprecipitation (co-IP), in situ proximity ligation assay (PLA), and in vitro kinase assay were conducted to reveal the underlying mechanism by which cyclin G2 regulates Y10 phosphorylation of LDHA. Further, the biological roles of cyclin G2 in cell proliferation, migration, invasion capacity, apoptosis, glycolysis, and immunomodulation were assessed through in vitro and in vivo functional experiments. Expressions of cyclin G2 and Foxp3 in glioma specimens was determined by immunohistochemistry.ResultsIn this study, we found that cyclin G2 impeded the interaction between LDHA and FGFR1, thereby decreasing Y10 phosphorylation of LDHA through FGFR1 catalysis. Cyclin G2 inhibited proliferation, migration, invasion capacity, and glycolysis and promoted apoptosis glioma cells via suppressing Y10 phosphorylation of LDHA. Moreover, we further verified that cyclin G2 reversed the immunosuppressive to antitumor immune microenvironment through inhibiting lactate production by glioma cells. Besides, cyclin G2 potentiated PD-1 blockade and exerted strong antitumor immunity in the glioma-bearing mice model.ConclusionsCyclin G2 acts as a potent tumor suppressor in glioma and enhances responses to immunotherapy. Our findings may be helpful in selecting glioma patients for immunotherapy trials in the future.
Highlights
Expression of aberrant cyclin G2 is a key factor contributing to cancer biological processes, including glioma
Through a series of in vivo and in vitro experiments, we found that cyclin G2 inhibits Y10 phosphorylation of Lactate dehydrogenase A (LDHA) catalyzed by fibroblast growth factor receptor 1 (FGFR1), inhibiting glycolysis and reverses the acidic tumor microenvironment (TME)
Cyclin G2 reduced LDHA Y10 phosphorylation catalyzed by FGFR1 Given that LDHA Y10 phosphorylation is catalyzed by FGFR1, HER2, and Src [21], to dissect the mechanism underlying the alterations in LDHA Y10 phosphorylation by cyclin G2, we initially examined the interaction between LDHA and upstream kinase affected by cyclin G2 by co-IP
Summary
Expression of aberrant cyclin G2 is a key factor contributing to cancer biological processes, including glioma. The potential underlying mechanisms of cyclin G2 in the glioma tumor immune microenvironment remain unclear. Li et al Journal of Experimental & Clinical Cancer Research (2021) 40:273 cells tend to metabolize glucose into lactate even in oxygen-rich conditions, known as the Warburg effect [12]. Metabolic reprograming is a pivotal mechanism shaping the tumor microenvironment (TME). Immune responses in the TME depend on the nature and concentration of factors, such as cytokines, reactive oxygen species (ROS), growth factors, and most importantly, diffusible metabolites (i.e., lactate) [13, 14]. Tyrosine 10 (Y10) phosphorylation of LDHA, which is rampant in diverse cancers, is correlated with several oncogenic tyrosine kinases, including fibroblast growth factor receptor 1 (FGFR1) [18]
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