BmK IT2 suppresses proliferation while differentially modulates migration and invasion of neural tumor cells: Association with down-regulation of functional VGSCs and transcriptional reprogramming.

Voltage-gated sodium channels (VGSCs) are emerging therapeutic targets for cancers including neural tumors such as neuroblastomas and gliomas. BmK IT2, a neurotoxic polypeptide from the scorpion Buthus martensii Karsch, is a known modulator of VGSCs. However, its potential antitumor effects and underlying mechanisms have not been reported. This study investigated the antitumor activity of recombinant BmK IT2 in mouse neuroblastoma (Neuro-2a) and human glioma (H4) cell lines. Electrophysiological analyses confirmed its canonical VGSC-modulating activity, characterized by a shift of the half-activation voltage to more negative potential, promoting channel activation, while suppressing peak sodium channels. BmK IT2 exhibited a dose-dependent anti-proliferative effect in both Neuro-2a and H4 cells, while modulating migratory and invasive behaviors in a cell line-specific manner: it promoted migration but inhibited invasion in Neuro-2a cells, whereas in H4 cells it enhanced invasion but did not affect migration consistently. Quantitative transcriptomics unveiled that BmK IT2 induces extensive transcriptional reprogramming of key pathways such as TNF/NF-κB and HIF-1 signaling. Mechanistically, the anti-proliferative effect was correlated with downregulation of VGSC subunits (Scn2a, Scn3a, Scn8a, Scn1b) and sphingolipid metabolism enzymes (ASAH1, UGCG) in Neuro-2a cells. Preliminary biosafety assessment showed that local intracranial administration of BmK IT2 did not induce significant systemic or histological toxicity. These findings suggest that BmK IT2 may influence proliferation, migration, and invasion of neural tumor cells in association with VGSC modulation and/or transcriptional reprogramming, and may serve as a molecular template for the development of novel anti-cancer peptides with multifaceted mechanisms.