HSP90B1-mediated plasma membrane localization of GLUT1 promotes radioresistance of glioblastomas.

Ionizing radiation is a popular and effective treatment option for glioblastoma (GBM). However, resistance to radiation therapy inevitably occurs during treatment. It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity. Here, we found that heat shock protein 90 beta family member 1 (HSP90B1) was significantly upregulated in radioresistant GBM cell lines. More importantly, HSP90B1 promoted the localization of glucose transporter type 1, a key rate-limiting factor of glycolysis, on the plasma membrane, which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells. These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients, a potential new approach to the treatment of glioblastoma.

Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation.

EGFRT790M mutation causes resistance to the first-generation tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, the therapeutic options for sensitizing first TKIs and delaying the emergence of EGFRT790M mutant are limited. In this study, we show that quercetin directly binds with glucose-6-phosphate dehydrogenase (G6PD) and inhibits its enzymatic activity through competitively abrogating NADP+ binding in the catalytic domain. This inhibition subsequently reduces intracellular NADPH levels, resulting in insufficient substrate for methionine reductase A (MsrA) to reduce M790 oxidization of EGFRT790M and inducing the degradation of EGFRT790M. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFRT790M-harboring NSCLCs and delays the acquisition of the EGFRT790M mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFRT790M mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFRT790M-driven TKI resistance by directly targeting G6PD.

NH4+ Toxicity, Which Is Mainly Determined by the High NH4+/K+ Ratio, Is Alleviated by CIPK23 in Arabidopsis.

Ammonium (NH4+) toxicity is always accompanied by ion imbalances, and NH4+ and potassium (K+) exhibit a competitive correlation in their uptake and transport processes. In Arabidopsis thaliana, the typical leaf chlorosis phenotype in the knockout mutant of calcineurin B-like interacting protein kinase 23 (CIPK23) is high-NH4+-dependent under low-K+ condition. However, the correlation of K+ and NH4+ in the occurrence of leaf chlorosis in the cipk23 mutant has not been deeply elucidated. Here, a modified hydroponic experimental system with different gradients of NH4+ and K+ was applied. Comparative treatments showed that NH4+ toxicity, which is triggered mainly by the high ratio of NH4+ to K+ (NH4+/K+ ≥ 10:1 for cipk23) but not by the absolute concentrations of the ions, results in leaf chlorosis. Under high NH4+/K+ ratios, CIPK23 is upregulated abundantly in leaves and roots, which efficiently reduces the leaf chlorosis by regulating the contents of NH4+ and K+ in plant shoots, while promoting the elongation of primary and lateral roots. Physiological data were obtained to further confirm the role CIPK23 in alleviating NH4+ toxicity. Taken all together, CIPK23 might function in different tissues to reduce stress-induced NH4+ toxicity associated with high NH4+/K+ ratios by regulating the NH4+-K+ balance in Arabidopsis.