Dexamethasone activates c-Jun NH2-terminal kinase (JNK) which interacts with GR and protects it from ubiquitin-mediated degradation in NSCLC cells

Dexamethasone-mediated pharmacological activation of the glucocorticoid receptor (GR) is widely used in the treatment regimen of hematological malignancies and solid cancers. However, DEX sensitivity towards patients primarily depends on the endogenous protein levels of GR. We observed that DEX treatment leads to an increase in GR protein levels despite inhibition of neo-protein synthesis in non -small cell lung cancer (NSCLC) cells. Mechanistically, DEX-stimulation concomitantly increased the JNK phosphorylation and GR protein levels, however the JNK stimulation preceds GR upregulation. Moreover, we also observed that DEX-mediated phosphorylation is partially mediated by upregulation in MEKK1 phosphorylation. Further, GR protein levels were significantly decreased in JNK inhibitor (JNKi, SP600125) treated cells whereas MG132 treatment restored GR levels indicating that DEX induced JNK activity regulated the GR protein levels through proteasomal-degradation pathway. Next, we showed that DEX led to JNK activation which physically interacts with GR and protects it from ubiquitination-mediated degradation. Furthermore, at basal level GR interacts with JNK in cytoplasm whereas upon DEX stimulation GR and pJNK both localized to nucleus and interact with each other. Next, we show that JNK-mediated GR stabilization affects its nuclear transcriptional functional activity in NSCLC cells. In line with these in vitro data, patient dataset analysis also shows that increased levels of both JNK and GR contributes towards better prognosis of NSCLC patients. Taken together, our data shows that DEX treatment may lead to positive feedback regulation of GR by activating JNK and thus highlights impor-tance of GR-JNK crosstalk in NSCLC.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

Dexamethasone treatment leads to an increase in glucocorticoid receptor (GR) protein levels in non-small cell lung cancer (NSCLC) cells through JNK activation. JNK phosphorylation precedes GR upregulation, and JNK-mediated GR stabilization affects its nuclear transcriptional functional activity in NSCLC cells. Increased levels of both JNK and GR contribute towards better prognosis of NSCLC patients.