Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib.
We recently demonstrated that caveolae, vesicular flask-shaped invaginations of the plasma membrane, represent novel therapeutic targets in multiple myeloma. In the present study, we demonstrate that vascular endothelial growth factor (VEGF) triggers Src-dependent phosphorylation of caveolin-1, which is required for p130(Cas) phosphorylation and multiple myeloma cell migration. Conversely, depletion of caveolin-1 by antisense methodology abrogates p130(Cas) phosphorylation and VEGF-triggered multiple myeloma cell migration. The proteasome inhibitor bortezomib both inhibited VEGF-triggered caveolin-1 phosphorylation and markedly decreased caveolin-1 expression. Consequently, bortezomib inhibited VEGF-induced multiple myeloma 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 human umbilical vascular endothelial cells. Taken together, these studies demonstrate the requirement of caveolae for VEGF-triggered multiple myeloma cell migration and identify caveolin-1 in multiple myeloma cells and human umbilical vascular endothelial cells as a molecular target of bortezomib.
Podar
Klaus
K
Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Shringarpure
Reshma
R
Tai
Yu-Tzu
YT
Simoncini
Melissa
M
Sattler
Martin
M
Ishitsuka
Kenji
K
Richardson
Paul G
PG
Hideshima
Teru
T
Chauhan
Dharminder
D
Anderson
Kenneth C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D050719:Crk-Associated Substrate Protein; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D050717:Retinoblastoma-Like Protein p130; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; C493841:BCAR1 protein, human; D001897:Boronic Acids; C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D050719:Crk-Associated Substrate Protein; D011506:Proteins; D011719:Pyrazines; D011994:Recombinant Proteins; D050717:Retinoblastoma-Like Protein p130; D042461:Vascular Endothelial Growth Factor A; D014443:Tyrosine; D000069286:Bortezomib; D019061:src-Family Kinases