We recently demonstrated that caveolae, vesicular flask-shaped invaginations of the plasma membrane represent novel therapeutic targets in multiple myeloma (MM). In the present study, we demonstrate that vascular endothelial growth factor (VEGF) triggers Src-dependent phosphorylation of caveolin-1, which is required for p130Cas phosphorylation and MM cell migration. Conversely, depletion of caveolin-1 by antisense methodology abrogates p130Cas phosphorylation and VEGF-triggered MM cell migration. The proteasome inhibitor bortezomib, both inhibited VEGF-triggered caveolin-1 phosphorylation and markedly decreased caveolin-1 expression. Consequently, bortezomib inhibited VEGF- induced MM cell migration. Bortezomib also decreased VEGF secretion in the bone marrow microenvironment and inhibited VEGF-triggered tyrosine phosphorylation of caveolin-1, migration, and survival in HUVECs.

Taken together, these studies demonstrate the requirement of caveolae for VEGF-triggered MM cell migration and identify caveolin-1 in MM cells and HUVECs as a molecular target of bortezomib.

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