Glucocorticoid receptor activated by dexamethasone promotes the chemoresistance and stemness of lung cancer.

[AIMS] Glucocorticoids (GCs) such as dexamethasone are routinely used in patients to alleviate side effects of chemotherapeutic agents or symptoms caused by advanced cancer. However, growing evidences have found glucocorticoids-induced chemoresistance in solid tumors, while the potential effects and underlying mechanisms are still remained unclearly. This study aimed to reveal the underlying mechanism of glucocorticoids-induced chemoresistance in lung cancer.

[METHODS] Effects of dexamethasone on chemotherapy efficiency and stemness properties were tested both in vitro and in vivo assays. Underlying mechanism of dexamethasone was revealed by western blot, protein immunoprecipitation, molecular dynamics simulation, high-resolution mass spectrometry detection and RNA-sequencing. Prognostic value of glucocorticoid receptor (GR) activation in lung cancer patients was assessed through transcriptomic analyses of public datasets.

[RESULTS] Pre-treatment with dexamethasone significantly suppressed the apoptosis mediated by multiple chemotherapeutic agents in lung cancer cells. Pulmonary metastatic mouse models showed dexamethasone pre-treatment markedly reduced the anti-tumor efficiency of paclitaxel. Stemness-related properties of lung cancer were significantly improved after dexamethasone treatment, which manifested with enhanced self-renewal capability, improved chemoresistance, and increased tumor initiating potential in vivo. Moreover, we revealed the chemoresistance and stemness properties induced by dexamethasone were depended on GR-mediated nuclear translocation of β-catenin. The N-terminal domain (NTD) and activation function 2 (AF2) region of GR mediated the major contribution in the interaction with β-catenin. Analyses of clinical samples from TCGA-LUAD and GEO datasets demonstrated GR activation was associated with worse survival and less benefits from chemotherapy in lung cancer patients.

[CONCLUSIONS] These results revealed dexamethasone could promote chemoresistance and stemness in lung cancer by inducing nuclear-translocation of GR/β-catenin complex. In the long run, more cautions are needed when glucocorticoids are prescribed to patients during chemotherapy.