Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4

Yan Xie, Dennis W. Wolff, Taotao Wei, Bo Wang, Caishu Deng, Joseph K. Kirui, Haihong Jiang, Jianbing Qin, Peter W. Abel, Yaping Tu

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Aberrant signaling through G-protein coupled receptors promotes metastasis, the major cause of breast cancer death. We identified regulator of G-protein signaling 4 (RGS4) as a novel suppressor of breast cancer migration and invasion, important steps of metastatic cascades. By blocking signals initiated through Gi-coupled receptors, such as protease-activated receptor 1 and CXC chemokine receptor 4, RGS4 disrupted Rac1-dependent lamellipodia formation, a key step involved in cancer migration and invasion. RGS4 has GTPase-activating protein (GAP) activity, which inhibits G-protein coupled receptor signaling by deactivating G-proteins. An RGS4 GAP-deficient mutant failed to inhibit migration and invasion of breast cancer cells in both in vitro assays and a mouse xenograft model. Interestingly, both established breast cancer cell lines and human breast cancer specimens showed that the highest levels of RGS4 protein were expressed in normal breast epithelia and that RGS4 down-regulation by proteasome degradation is an index of breast cancer invasiveness. Proteasome blockade increased endogenous RGS4 protein to levels that markedly inhibit breast cancer cell migration and invasion, which was reversed by an RGS4-targeted short hairpin RNA. Our findings point to the existence of a mechanism for posttranslational regulation of RGS4 function, which may have important implications for the acquisition of a metastatic phenotype by breast cancer cells. Preventing degradation of RGS4 protein should attenuate aberrant signal inputs from multiple Gi-coupled receptors, thereby retarding the spread of breast cancer cells and making them targets for surgery, radiation, and immune treatment.

Original languageEnglish
Pages (from-to)5743-5751
Number of pages9
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009

Fingerprint

GTP-Binding Protein Regulators
Proteasome Endopeptidase Complex
Breast Neoplasms
RGS Proteins
GTPase-Activating Proteins
G-Protein-Coupled Receptors
PAR-1 Receptor
CXCR4 Receptors
Pseudopodia
GTP-Binding Proteins
Heterografts
Small Interfering RNA
Cell Movement
Breast
Down-Regulation
Epithelium
Radiation
Neoplasm Metastasis
Phenotype

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4. / Xie, Yan; Wolff, Dennis W.; Wei, Taotao; Wang, Bo; Deng, Caishu; Kirui, Joseph K.; Jiang, Haihong; Qin, Jianbing; Abel, Peter W.; Tu, Yaping.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5743-5751.

Research output: Contribution to journalArticle

Xie, Yan ; Wolff, Dennis W. ; Wei, Taotao ; Wang, Bo ; Deng, Caishu ; Kirui, Joseph K. ; Jiang, Haihong ; Qin, Jianbing ; Abel, Peter W. ; Tu, Yaping. / Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5743-5751.
@article{8e59006276cf4c9cb0237930e960cb7b,
title = "Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4",
abstract = "Aberrant signaling through G-protein coupled receptors promotes metastasis, the major cause of breast cancer death. We identified regulator of G-protein signaling 4 (RGS4) as a novel suppressor of breast cancer migration and invasion, important steps of metastatic cascades. By blocking signals initiated through Gi-coupled receptors, such as protease-activated receptor 1 and CXC chemokine receptor 4, RGS4 disrupted Rac1-dependent lamellipodia formation, a key step involved in cancer migration and invasion. RGS4 has GTPase-activating protein (GAP) activity, which inhibits G-protein coupled receptor signaling by deactivating G-proteins. An RGS4 GAP-deficient mutant failed to inhibit migration and invasion of breast cancer cells in both in vitro assays and a mouse xenograft model. Interestingly, both established breast cancer cell lines and human breast cancer specimens showed that the highest levels of RGS4 protein were expressed in normal breast epithelia and that RGS4 down-regulation by proteasome degradation is an index of breast cancer invasiveness. Proteasome blockade increased endogenous RGS4 protein to levels that markedly inhibit breast cancer cell migration and invasion, which was reversed by an RGS4-targeted short hairpin RNA. Our findings point to the existence of a mechanism for posttranslational regulation of RGS4 function, which may have important implications for the acquisition of a metastatic phenotype by breast cancer cells. Preventing degradation of RGS4 protein should attenuate aberrant signal inputs from multiple Gi-coupled receptors, thereby retarding the spread of breast cancer cells and making them targets for surgery, radiation, and immune treatment.",
author = "Yan Xie and Wolff, {Dennis W.} and Taotao Wei and Bo Wang and Caishu Deng and Kirui, {Joseph K.} and Haihong Jiang and Jianbing Qin and Abel, {Peter W.} and Yaping Tu",
year = "2009",
month = "7",
day = "15",
doi = "10.1158/0008-5472.CAN-08-3564",
language = "English",
volume = "69",
pages = "5743--5751",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4

AU - Xie, Yan

AU - Wolff, Dennis W.

AU - Wei, Taotao

AU - Wang, Bo

AU - Deng, Caishu

AU - Kirui, Joseph K.

AU - Jiang, Haihong

AU - Qin, Jianbing

AU - Abel, Peter W.

AU - Tu, Yaping

PY - 2009/7/15

Y1 - 2009/7/15

N2 - Aberrant signaling through G-protein coupled receptors promotes metastasis, the major cause of breast cancer death. We identified regulator of G-protein signaling 4 (RGS4) as a novel suppressor of breast cancer migration and invasion, important steps of metastatic cascades. By blocking signals initiated through Gi-coupled receptors, such as protease-activated receptor 1 and CXC chemokine receptor 4, RGS4 disrupted Rac1-dependent lamellipodia formation, a key step involved in cancer migration and invasion. RGS4 has GTPase-activating protein (GAP) activity, which inhibits G-protein coupled receptor signaling by deactivating G-proteins. An RGS4 GAP-deficient mutant failed to inhibit migration and invasion of breast cancer cells in both in vitro assays and a mouse xenograft model. Interestingly, both established breast cancer cell lines and human breast cancer specimens showed that the highest levels of RGS4 protein were expressed in normal breast epithelia and that RGS4 down-regulation by proteasome degradation is an index of breast cancer invasiveness. Proteasome blockade increased endogenous RGS4 protein to levels that markedly inhibit breast cancer cell migration and invasion, which was reversed by an RGS4-targeted short hairpin RNA. Our findings point to the existence of a mechanism for posttranslational regulation of RGS4 function, which may have important implications for the acquisition of a metastatic phenotype by breast cancer cells. Preventing degradation of RGS4 protein should attenuate aberrant signal inputs from multiple Gi-coupled receptors, thereby retarding the spread of breast cancer cells and making them targets for surgery, radiation, and immune treatment.

AB - Aberrant signaling through G-protein coupled receptors promotes metastasis, the major cause of breast cancer death. We identified regulator of G-protein signaling 4 (RGS4) as a novel suppressor of breast cancer migration and invasion, important steps of metastatic cascades. By blocking signals initiated through Gi-coupled receptors, such as protease-activated receptor 1 and CXC chemokine receptor 4, RGS4 disrupted Rac1-dependent lamellipodia formation, a key step involved in cancer migration and invasion. RGS4 has GTPase-activating protein (GAP) activity, which inhibits G-protein coupled receptor signaling by deactivating G-proteins. An RGS4 GAP-deficient mutant failed to inhibit migration and invasion of breast cancer cells in both in vitro assays and a mouse xenograft model. Interestingly, both established breast cancer cell lines and human breast cancer specimens showed that the highest levels of RGS4 protein were expressed in normal breast epithelia and that RGS4 down-regulation by proteasome degradation is an index of breast cancer invasiveness. Proteasome blockade increased endogenous RGS4 protein to levels that markedly inhibit breast cancer cell migration and invasion, which was reversed by an RGS4-targeted short hairpin RNA. Our findings point to the existence of a mechanism for posttranslational regulation of RGS4 function, which may have important implications for the acquisition of a metastatic phenotype by breast cancer cells. Preventing degradation of RGS4 protein should attenuate aberrant signal inputs from multiple Gi-coupled receptors, thereby retarding the spread of breast cancer cells and making them targets for surgery, radiation, and immune treatment.

UR - http://www.scopus.com/inward/record.url?scp=67651006540&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651006540&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-08-3564

DO - 10.1158/0008-5472.CAN-08-3564

M3 - Article

VL - 69

SP - 5743

EP - 5751

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 14

ER -