Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib

Klaus Podar; Reshma Shringarpure; Yu-Tzu Tai; Melissa Simoncini; Martin Sattler; Kenji Ishitsuka; Paul G Richardson; Teru Hideshima; Dharminder Chauhan; Kenneth C Anderson

doi:10.1158/0008-5472.CAN-04-0124

Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib

Klaus Podar, Reshma Shringarpure, Yu-Tzu Tai, Melissa Simoncini, Martin Sattler, Kenji Ishitsuka, Paul G Richardson, Teru Hideshima, Dharminder Chauhan, Kenneth C Anderson

Research output: Journal article (peer-reviewed) › Journal article

90 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	7500-7506
Number of pages	7
Journal	Cancer Research
Volume	64
Issue number	20
DOIs	https://doi.org/10.1158/0008-5472.CAN-04-0124
Publication status	Published - 15 Oct 2004
Externally published	Yes

Keywords

Antineoplastic Agents/pharmacology
Bone Marrow/metabolism
Boronic Acids/pharmacology
Bortezomib
Caveolin 1
Caveolins/biosynthesis
Cell Line, Tumor
Cell Movement/drug effects
Crk-Associated Substrate Protein
Endothelium, Vascular/cytology
Humans
Multiple Myeloma/genetics
Phosphorylation
Proteins/metabolism
Pyrazines/pharmacology
Recombinant Proteins/pharmacology
Retinoblastoma-Like Protein p130
Transfection
Tyrosine/metabolism
Vascular Endothelial Growth Factor A/antagonists & inhibitors
src-Family Kinases/metabolism

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10.1158/0008-5472.CAN-04-0124

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Podar, K., Shringarpure, R., Tai, Y.-T., Simoncini, M., Sattler, M., Ishitsuka, K., Richardson, P. G., Hideshima, T., Chauhan, D., & Anderson, K. C. (2004). Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib. Cancer Research, 64(20), 7500-7506. https://doi.org/10.1158/0008-5472.CAN-04-0124

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title = "Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib",

abstract = "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.",

keywords = "Antineoplastic Agents/pharmacology, Bone Marrow/metabolism, Boronic Acids/pharmacology, Bortezomib, Caveolin 1, Caveolins/biosynthesis, Cell Line, Tumor, Cell Movement/drug effects, Crk-Associated Substrate Protein, Endothelium, Vascular/cytology, Humans, Multiple Myeloma/genetics, Phosphorylation, Proteins/metabolism, Pyrazines/pharmacology, Recombinant Proteins/pharmacology, Retinoblastoma-Like Protein p130, Transfection, Tyrosine/metabolism, Vascular Endothelial Growth Factor A/antagonists & inhibitors, src-Family Kinases/metabolism",

author = "Klaus Podar and Reshma Shringarpure and Yu-Tzu Tai and Melissa Simoncini and Martin Sattler and Kenji Ishitsuka and Richardson, {Paul G} and Teru Hideshima and Dharminder Chauhan and Anderson, {Kenneth C}",

year = "2004",

month = oct,

day = "15",

doi = "10.1158/0008-5472.CAN-04-0124",

language = "English",

volume = "64",

pages = "7500--7506",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

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Podar, K, Shringarpure, R, Tai, Y-T, Simoncini, M, Sattler, M, Ishitsuka, K, Richardson, PG, Hideshima, T, Chauhan, D & Anderson, KC 2004, 'Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib', Cancer Research, vol. 64, no. 20, pp. 7500-7506. https://doi.org/10.1158/0008-5472.CAN-04-0124

TY - JOUR

T1 - Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib

AU - Podar, Klaus

AU - Shringarpure, Reshma

AU - Tai, Yu-Tzu

AU - Simoncini, Melissa

AU - Sattler, Martin

AU - Ishitsuka, Kenji

AU - Richardson, Paul G

AU - Hideshima, Teru

AU - Chauhan, Dharminder

AU - Anderson, Kenneth C

PY - 2004/10/15

Y1 - 2004/10/15

N2 - 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.

AB - 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.

KW - Antineoplastic Agents/pharmacology

KW - Bone Marrow/metabolism

KW - Boronic Acids/pharmacology

KW - Bortezomib

KW - Caveolin 1

KW - Caveolins/biosynthesis

KW - Cell Line, Tumor

KW - Cell Movement/drug effects

KW - Crk-Associated Substrate Protein

KW - Endothelium, Vascular/cytology

KW - Humans

KW - Multiple Myeloma/genetics

KW - Phosphorylation

KW - Proteins/metabolism

KW - Pyrazines/pharmacology

KW - Recombinant Proteins/pharmacology

KW - Retinoblastoma-Like Protein p130

KW - Transfection

KW - Tyrosine/metabolism

KW - Vascular Endothelial Growth Factor A/antagonists & inhibitors

KW - src-Family Kinases/metabolism

UR - http://www.scopus.com/inward/record.url?scp=5644225628&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-04-0124

DO - 10.1158/0008-5472.CAN-04-0124

M3 - Journal article

C2 - 15492276

SN - 0008-5472

VL - 64

SP - 7500

EP - 7506

JO - Cancer Research

JF - Cancer Research

IS - 20

ER -

Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib

Abstract

Keywords

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