Disrupting VDAC1–tubulin interaction uncovers crosstalk between mitochondrial and microtubule functions with implication to cancer therapy

Tubulin, a key component of the microtubule (MT) cytoskeleton, interacts with the mitochondrial gatekeeper protein VDAC1. Using a peptide array, we identified four VDAC1-binding sites in α-tubulin-1B. Synthetic peptides corresponding to these sequences bound purified VDAC1, disrupted MT polymerization and structure, and impaired MT function. In cells, the peptides disrupted the MT network, reduced tubulin and glucose transporter (Glut-1) expression, induced p53 and VDAC1 overexpression, triggered apoptosis, and elevated cytosolic Ca²⁺ and reactive oxygen species. In a glioblastoma mouse model, an α-tubulin–derived peptide inhibited tumor growth, reduced proliferation, altered the tumor microenvironment and inflammation, decreased tubulin and Glut-1 expression, and increased VDAC1 and p53 expression. Finally, the anticancer MT-stabilizing agent paclitaxel produced similar effects as the α-tubulin-derived peptide in both cells and tumors. These findings suggest that combining MT destabilization with targeting the VDAC1–tubulin interaction may represent a potentially anticancer strategy. VDAC1-binding tubulin-derived peptide disrupted microtubule polymerization and structure. The peptide reduced tubulin and glucose transporter expression. The peptide induced p53 and VDAC1 overexpression. The peptide triggered apoptosis, and elevated cytosolic Ca²⁺ and reactive oxygen species. In a glioblastoma mouse model, the peptide inhibited tumor growth, reduced proliferation. Peptide targeting the VDAC1–tubulin interaction represents a potentially novel anticancer strategy.