Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion

Yan Xie, Peter W. Abel, Joseph K. Kirui, Caishu Deng, Poonam Sharma, Dennis W. Wolff, Myron Lee Toews, Yaping Tu

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Metastasis is the major cause of breast cancer mortality. We recently reported that aberrant G-protein coupled receptor (GPCR) signaling promotes breast cancer metastasis by enhancing cancer cell migration and invasion. Phosphatidylinositol 3-kinase γ (PI3Kγ) is specifically activated by GPCRs. The goal of the present study was to determine the role of PI3Kγ in breast cancer cell migration and invasion. Immunohistochemical staining showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma when compared to adjacent benign breast tissue or ductal carcinoma in situ. PI3Kγ was also detected in metastatic breast cancer cells, but not in normal breast epithelial cell line or in non-metastatic breast cancer cells. In contrast, PI3K isoforms α, β and δ were ubiquitously expressed in these cell lines. Overexpression of recombinant PI3Kγ enhanced the metastatic ability of non-metastatic breast cancer cells. Conversely, migration and invasion of metastatic breast cancer cells were inhibited by a PI3Kγ inhibitor or by siRNA knockdown of PI3Kγ but not by inhibitors or siRNAs of PI3Kα or PI3Kβ. Lamellipodia formation is a key step in cancer metastasis, and PI3Kγ blockade disrupted lamellipodia formation induced by the activation of GPCRs such as CXC chemokine receptor 4 and protease-activated receptor 1, but not by the epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that upregulated PI3Kγ conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that PI3Kγ may be a novel therapeutic target for development of chemotherapeutic agents to prevent breast cancer metastasis.

Original languageEnglish (US)
Pages (from-to)1454-1462
Number of pages9
JournalBiochemical Pharmacology
Volume85
Issue number10
DOIs
StatePublished - May 15 2013

Fingerprint

Phosphatidylinositol 3-Kinase
1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Cell Movement
Phosphotransferases
Cells
Breast Neoplasms
Neoplasm Metastasis
Pseudopodia
PAR-1 Receptor
CXCR4 Receptors
Cell Line
Carcinoma, Intraductal, Noninfiltrating
Receptor Protein-Tyrosine Kinases
G-Protein-Coupled Receptors
Epidermal Growth Factor

Keywords

  • Breast cancer
  • Lamellipodia
  • Metastasis
  • Migration and invasion
  • PI3Kγ

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion. / Xie, Yan; Abel, Peter W.; Kirui, Joseph K.; Deng, Caishu; Sharma, Poonam; Wolff, Dennis W.; Toews, Myron Lee; Tu, Yaping.

In: Biochemical Pharmacology, Vol. 85, No. 10, 15.05.2013, p. 1454-1462.

Research output: Contribution to journalArticle

Xie, Yan ; Abel, Peter W. ; Kirui, Joseph K. ; Deng, Caishu ; Sharma, Poonam ; Wolff, Dennis W. ; Toews, Myron Lee ; Tu, Yaping. / Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion. In: Biochemical Pharmacology. 2013 ; Vol. 85, No. 10. pp. 1454-1462.
@article{a1d5aa4b474946ff8ebffb33031333ed,
title = "Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion",
abstract = "Metastasis is the major cause of breast cancer mortality. We recently reported that aberrant G-protein coupled receptor (GPCR) signaling promotes breast cancer metastasis by enhancing cancer cell migration and invasion. Phosphatidylinositol 3-kinase γ (PI3Kγ) is specifically activated by GPCRs. The goal of the present study was to determine the role of PI3Kγ in breast cancer cell migration and invasion. Immunohistochemical staining showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma when compared to adjacent benign breast tissue or ductal carcinoma in situ. PI3Kγ was also detected in metastatic breast cancer cells, but not in normal breast epithelial cell line or in non-metastatic breast cancer cells. In contrast, PI3K isoforms α, β and δ were ubiquitously expressed in these cell lines. Overexpression of recombinant PI3Kγ enhanced the metastatic ability of non-metastatic breast cancer cells. Conversely, migration and invasion of metastatic breast cancer cells were inhibited by a PI3Kγ inhibitor or by siRNA knockdown of PI3Kγ but not by inhibitors or siRNAs of PI3Kα or PI3Kβ. Lamellipodia formation is a key step in cancer metastasis, and PI3Kγ blockade disrupted lamellipodia formation induced by the activation of GPCRs such as CXC chemokine receptor 4 and protease-activated receptor 1, but not by the epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that upregulated PI3Kγ conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that PI3Kγ may be a novel therapeutic target for development of chemotherapeutic agents to prevent breast cancer metastasis.",
keywords = "Breast cancer, Lamellipodia, Metastasis, Migration and invasion, PI3Kγ",
author = "Yan Xie and Abel, {Peter W.} and Kirui, {Joseph K.} and Caishu Deng and Poonam Sharma and Wolff, {Dennis W.} and Toews, {Myron Lee} and Yaping Tu",
year = "2013",
month = "5",
day = "15",
doi = "10.1016/j.bcp.2013.03.001",
language = "English (US)",
volume = "85",
pages = "1454--1462",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "10",

}

TY - JOUR

T1 - Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion

AU - Xie, Yan

AU - Abel, Peter W.

AU - Kirui, Joseph K.

AU - Deng, Caishu

AU - Sharma, Poonam

AU - Wolff, Dennis W.

AU - Toews, Myron Lee

AU - Tu, Yaping

PY - 2013/5/15

Y1 - 2013/5/15

N2 - Metastasis is the major cause of breast cancer mortality. We recently reported that aberrant G-protein coupled receptor (GPCR) signaling promotes breast cancer metastasis by enhancing cancer cell migration and invasion. Phosphatidylinositol 3-kinase γ (PI3Kγ) is specifically activated by GPCRs. The goal of the present study was to determine the role of PI3Kγ in breast cancer cell migration and invasion. Immunohistochemical staining showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma when compared to adjacent benign breast tissue or ductal carcinoma in situ. PI3Kγ was also detected in metastatic breast cancer cells, but not in normal breast epithelial cell line or in non-metastatic breast cancer cells. In contrast, PI3K isoforms α, β and δ were ubiquitously expressed in these cell lines. Overexpression of recombinant PI3Kγ enhanced the metastatic ability of non-metastatic breast cancer cells. Conversely, migration and invasion of metastatic breast cancer cells were inhibited by a PI3Kγ inhibitor or by siRNA knockdown of PI3Kγ but not by inhibitors or siRNAs of PI3Kα or PI3Kβ. Lamellipodia formation is a key step in cancer metastasis, and PI3Kγ blockade disrupted lamellipodia formation induced by the activation of GPCRs such as CXC chemokine receptor 4 and protease-activated receptor 1, but not by the epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that upregulated PI3Kγ conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that PI3Kγ may be a novel therapeutic target for development of chemotherapeutic agents to prevent breast cancer metastasis.

AB - Metastasis is the major cause of breast cancer mortality. We recently reported that aberrant G-protein coupled receptor (GPCR) signaling promotes breast cancer metastasis by enhancing cancer cell migration and invasion. Phosphatidylinositol 3-kinase γ (PI3Kγ) is specifically activated by GPCRs. The goal of the present study was to determine the role of PI3Kγ in breast cancer cell migration and invasion. Immunohistochemical staining showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma when compared to adjacent benign breast tissue or ductal carcinoma in situ. PI3Kγ was also detected in metastatic breast cancer cells, but not in normal breast epithelial cell line or in non-metastatic breast cancer cells. In contrast, PI3K isoforms α, β and δ were ubiquitously expressed in these cell lines. Overexpression of recombinant PI3Kγ enhanced the metastatic ability of non-metastatic breast cancer cells. Conversely, migration and invasion of metastatic breast cancer cells were inhibited by a PI3Kγ inhibitor or by siRNA knockdown of PI3Kγ but not by inhibitors or siRNAs of PI3Kα or PI3Kβ. Lamellipodia formation is a key step in cancer metastasis, and PI3Kγ blockade disrupted lamellipodia formation induced by the activation of GPCRs such as CXC chemokine receptor 4 and protease-activated receptor 1, but not by the epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that upregulated PI3Kγ conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that PI3Kγ may be a novel therapeutic target for development of chemotherapeutic agents to prevent breast cancer metastasis.

KW - Breast cancer

KW - Lamellipodia

KW - Metastasis

KW - Migration and invasion

KW - PI3Kγ

UR - http://www.scopus.com/inward/record.url?scp=84876679729&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876679729&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2013.03.001

DO - 10.1016/j.bcp.2013.03.001

M3 - Article

C2 - 23500535

AN - SCOPUS:84876679729

VL - 85

SP - 1454

EP - 1462

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 10

ER -