Tenvermectin B, a novel macrocyclic lactone antibiotic, suppresses glioblastoma progression by targeting RhoJ

Abstract

Background

The migratory and invasive behavior of glioblastoma (GBM) poses significant challenges for treatment, and the underlying mechanisms require further exploration. While macrolide antibiotics exhibit antitumor activity, the antitumor effects and molecular mechanisms of the novel macrolide TVM B remain unclear. This study aimed to investigate its efficacy against GBM and elucidate the mechanisms by which it modulates GBM cell migration and invasion.

Methods

First, the cytotoxicity of TVM B was evaluated using the MTT assay. In vivo, a xenograft mouse model was established, and the drug was administered via intraperitoneal injection. Western blot and pathological staining were performed to investigate the effects of TVM B on tumor growth. Used RNA-seq data to explore its potential mechanism of action, and performed molecular docking to identify potential targets. In vitro validation experiments included the wound healing assay, Transwell migration and invasion assays, Tube formation Assay, RT-qPCR, Western blot, flow cytometry for apoptosis detection, and immunofluorescence staining.

Results

In vitro, TVM B inhibited GBM cells proliferation, induced apoptosis, and suppressed migration and invasion. TVM B abrogated the angiogenic capacity of HUVECs. In vivo xenograft experiments showed that TVM B treatment reduced Ki67 positivity, decreased the expression of MMP9, MMP2, and p-FAK in tumor tissues, and HE staining of various organs revealed no obvious toxicity. Mechanistic studies showed TVM B regulated RhoJ to inhibit cytoskeletal dynamics and FAK/Src signaling, thereby suppressing cell migration and invasion via focal adhesion modulation.

Conclusion

This study for the first time demonstrates that TVM B regulates cytoskeletal homeostasis via RhoJ, inhibits cell proliferation, and affects the FAK/Src pathway to ultimately suppress migration and invasion of GBM cells.