RGS2 Promotes Brain Metastasis of Cisplatin-resistant Non-small Cell Lung Cancer through Caspase-1/IL-1beta Signaling Pathway.

[BACKGROUND] Brain metastases are a leading cause of mortality in non-small cell lung cancer (NSCLC) patients. Chemoresistance-induced metastasis remains a significant challenge in NSCLC. This study investigates whether cisplatin resistance enhances brain metastasis in NSCLC and examines the associated molecular mechanisms.

[METHODS] Cisplatin-resistant NSCLC cell lines were established. Their brain metastatic capacity was assessed using endothelial adhesion and blood-brain barrier (BBB) transmigration assay, as well as brain metastasis models. RNA-seq was performed to identify differentially expressed genes. The roles of key candidate molecules and mechanisms were validated through genetic and pharmacological inhibition approaches.

[RESULTS] Cisplatin-resistant NSCLC cells exhibited markedly enhanced brain metastatic capacity compared to their parental counterparts, with increased adhesion to brain endothelial cells and transmigration across the BBB in vitro, and more and larger brain metastatic lesions in vivo. RGS2 was revealed to be significantly upregulated in cisplatin-resistant and brain metastatic NSCLC cells, and was associated with an unfavorable prognosis in lung adenocarcinoma patients. RGS2 knockdown diminished the brain metastatic capacity of cisplatin-resistant NSCLC cells. Mechanistically, RGS2 activated the caspase-1/IL-1beta signaling pathway, promoting tumor cell-endothelial adhesion through VCAM-1 upregulation and compromising BBB integrity through Claudin-5 downregulation. Knockdown or pharmacological inhibition of caspase-1 counteracted these effects and mitigated RGS2-driven brain metastasis in vivo.

[CONCLUSIONS] Cisplatin resistance promotes brain metastasis in NSCLC through the RGS2/caspase-1/IL-1beta signaling. Targeting this pathway may offer a promising preventive strategy to reduce and curb brain metastasis in chemotherapy-resistant NSCLC. Moreover, RGS2 shows potential as a biomarker for monitoring and predicting NSCLC brain metastasis.