Autophagy promotes the brain metastasis of cisplatin-resistant lung cancer cells through the KLF4/KLF2/IL15 signaling pathway.

[BACKGROUND] Patients with lung cancer often develop brain metastases. The mechanism underlying the enhanced metastatic potential of drug-resistant lung cancer cells is unclear. Previously, we demonstrated that hypoxia-induced autophagy promotes cisplatin resistance. However, the effect of autophagy induction on pro-metastatic gene expression during drug resistance development has not been examined.

[OBJECTIVE] This study aimed to explore the molecular mechanism underlying autophagy mediated brain metastasis.

[METHODS] This study evaluated autophagy activation in cisplatin-resistant A549 (A549/DDP) and SK-MES-1 (SK-MES-1/DDP) cells. Differential gene analysis using GSE213102, GSE108214, GSE110495, GSE161116, and GSE73158 datasets revealed that IL-15 is a key component in the interplay between cisplatin resistance, autophagy, and brain metastasis. Next, the mechanism through which A549/DDP cells suppress natural killer (NK) cell activation was examined. The regulatory effects of the transcription factors KLF4 and KLF2 on IL15 were investigated using the luciferase reporter, chromatin immunoprecipitation, and DNA pull-down assays. In vivo brain metastasis was modeled in mice via carotid artery injection.

[RESULTS] Drug-resistant cells exhibited enhanced autophagy activation and ATG5 upregulation. IL-15 was downregulated in drug-resistant cells, impairing NK cell activation by downregulating IFN-γ, granzyme B, and perforin. Mechanistically, ATG5 upregulated KLF4/KLF2, which subsequently repressed IL15. KLF4 could directly bind the IL15 promoter, while KLF2 inhibited NF-κB (p50/p65)-driven IL15 transcription by interacting with PCAF. IL-15 overexpression suppressed the brain metastasis of A549/DDP cells in mice.

[CONCLUSION] The autophagy-ATG5-KLF4/KLF2 axis may downregulate IL-15 in cisplatin-resistant lung cancer cells, suppressing NK cell activation and promoting brain metastasis. These findings offer useful insights into the mechanisms underlying the brain metastasis of lung cancer and provide valuable reference for the development of preventive and therapeutic strategies for this pathological condition.