Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo

Pooja Hingorani, Wendong Zhang, Richard Gorlick, E. Anders Kolb

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Purpose: Pulmonary metastasis remains the major cause of mortality in osteosarcoma. Src tyrosine kinase is a key player involved in metastatic pathways in multiple human cancers. c-Src has been shown to be expressed and phosphorylated in osteosarcoma cell lines and inhibiting Src phosphorylation in these cells causes inhibition of the metastatic phenotype in vitro. We studied the effect of inhibition of Src phosphorylation in preventing the growth and development of pulmonary metastases in osteosarcoma. Experimental Design: Dasatinib, a dual Src-Abl kinase inhibitor, was used to study the effect of Src kinase inhibition on proliferation, adhesion, and invasion of osteosarcoma cell lines in vitro and in preventing the development of pulmonary metastases in a spontaneously metastatic mouse model. Results: In vitro, phosphorylation of Src and its downstream signaling molecules such as focal adhesion kinase, Crk-associated substrate, and c-Jun was inhibited at nanomolar concentrations of dasatinib. Dasatinib was not cytotoxic against the osteosarcoma cells with the IC50 ranging from 10 to 20 μmol/L but effectively inhibited the adhesion and migration of osteosarcoma cells at 10 to 100 nmol/L. However, in vivo, dasatinib did not inhibit the development of pulmonary metastases despite complete inhibition of Src phosphorylation in the primary tumors. No effect was seen in the primary tumor growth and the degree of apoptosis. Conclusions: These results suggest that Src kinase activation might not be the primary pathway involved in the development of pulmonary metastases in osteosarcoma.

Original languageEnglish (US)
Pages (from-to)3416-3422
Number of pages7
JournalClinical Cancer Research
Volume15
Issue number10
DOIs
StatePublished - May 15 2009

Fingerprint

Osteosarcoma
Phosphorylation
src-Family Kinases
Neoplasm Metastasis
Lung
Crk-Associated Substrate Protein
Cell Line
Focal Adhesion Protein-Tyrosine Kinases
Neoplasms
In Vitro Techniques
Growth and Development
Inhibitory Concentration 50
Cell Movement
Research Design
Apoptosis
Phenotype
Mortality
Dasatinib
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo. / Hingorani, Pooja; Zhang, Wendong; Gorlick, Richard; Kolb, E. Anders.

In: Clinical Cancer Research, Vol. 15, No. 10, 15.05.2009, p. 3416-3422.

Research output: Contribution to journalArticle

Hingorani, Pooja ; Zhang, Wendong ; Gorlick, Richard ; Kolb, E. Anders. / Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 10. pp. 3416-3422.
@article{9cac94d7e5ca4547b0ae010111ba02be,
title = "Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo",
abstract = "Purpose: Pulmonary metastasis remains the major cause of mortality in osteosarcoma. Src tyrosine kinase is a key player involved in metastatic pathways in multiple human cancers. c-Src has been shown to be expressed and phosphorylated in osteosarcoma cell lines and inhibiting Src phosphorylation in these cells causes inhibition of the metastatic phenotype in vitro. We studied the effect of inhibition of Src phosphorylation in preventing the growth and development of pulmonary metastases in osteosarcoma. Experimental Design: Dasatinib, a dual Src-Abl kinase inhibitor, was used to study the effect of Src kinase inhibition on proliferation, adhesion, and invasion of osteosarcoma cell lines in vitro and in preventing the development of pulmonary metastases in a spontaneously metastatic mouse model. Results: In vitro, phosphorylation of Src and its downstream signaling molecules such as focal adhesion kinase, Crk-associated substrate, and c-Jun was inhibited at nanomolar concentrations of dasatinib. Dasatinib was not cytotoxic against the osteosarcoma cells with the IC50 ranging from 10 to 20 μmol/L but effectively inhibited the adhesion and migration of osteosarcoma cells at 10 to 100 nmol/L. However, in vivo, dasatinib did not inhibit the development of pulmonary metastases despite complete inhibition of Src phosphorylation in the primary tumors. No effect was seen in the primary tumor growth and the degree of apoptosis. Conclusions: These results suggest that Src kinase activation might not be the primary pathway involved in the development of pulmonary metastases in osteosarcoma.",
author = "Pooja Hingorani and Wendong Zhang and Richard Gorlick and Kolb, {E. Anders}",
year = "2009",
month = "5",
day = "15",
doi = "10.1158/1078-0432.CCR-08-1657",
language = "English (US)",
volume = "15",
pages = "3416--3422",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo

AU - Hingorani, Pooja

AU - Zhang, Wendong

AU - Gorlick, Richard

AU - Kolb, E. Anders

PY - 2009/5/15

Y1 - 2009/5/15

N2 - Purpose: Pulmonary metastasis remains the major cause of mortality in osteosarcoma. Src tyrosine kinase is a key player involved in metastatic pathways in multiple human cancers. c-Src has been shown to be expressed and phosphorylated in osteosarcoma cell lines and inhibiting Src phosphorylation in these cells causes inhibition of the metastatic phenotype in vitro. We studied the effect of inhibition of Src phosphorylation in preventing the growth and development of pulmonary metastases in osteosarcoma. Experimental Design: Dasatinib, a dual Src-Abl kinase inhibitor, was used to study the effect of Src kinase inhibition on proliferation, adhesion, and invasion of osteosarcoma cell lines in vitro and in preventing the development of pulmonary metastases in a spontaneously metastatic mouse model. Results: In vitro, phosphorylation of Src and its downstream signaling molecules such as focal adhesion kinase, Crk-associated substrate, and c-Jun was inhibited at nanomolar concentrations of dasatinib. Dasatinib was not cytotoxic against the osteosarcoma cells with the IC50 ranging from 10 to 20 μmol/L but effectively inhibited the adhesion and migration of osteosarcoma cells at 10 to 100 nmol/L. However, in vivo, dasatinib did not inhibit the development of pulmonary metastases despite complete inhibition of Src phosphorylation in the primary tumors. No effect was seen in the primary tumor growth and the degree of apoptosis. Conclusions: These results suggest that Src kinase activation might not be the primary pathway involved in the development of pulmonary metastases in osteosarcoma.

AB - Purpose: Pulmonary metastasis remains the major cause of mortality in osteosarcoma. Src tyrosine kinase is a key player involved in metastatic pathways in multiple human cancers. c-Src has been shown to be expressed and phosphorylated in osteosarcoma cell lines and inhibiting Src phosphorylation in these cells causes inhibition of the metastatic phenotype in vitro. We studied the effect of inhibition of Src phosphorylation in preventing the growth and development of pulmonary metastases in osteosarcoma. Experimental Design: Dasatinib, a dual Src-Abl kinase inhibitor, was used to study the effect of Src kinase inhibition on proliferation, adhesion, and invasion of osteosarcoma cell lines in vitro and in preventing the development of pulmonary metastases in a spontaneously metastatic mouse model. Results: In vitro, phosphorylation of Src and its downstream signaling molecules such as focal adhesion kinase, Crk-associated substrate, and c-Jun was inhibited at nanomolar concentrations of dasatinib. Dasatinib was not cytotoxic against the osteosarcoma cells with the IC50 ranging from 10 to 20 μmol/L but effectively inhibited the adhesion and migration of osteosarcoma cells at 10 to 100 nmol/L. However, in vivo, dasatinib did not inhibit the development of pulmonary metastases despite complete inhibition of Src phosphorylation in the primary tumors. No effect was seen in the primary tumor growth and the degree of apoptosis. Conclusions: These results suggest that Src kinase activation might not be the primary pathway involved in the development of pulmonary metastases in osteosarcoma.

UR - http://www.scopus.com/inward/record.url?scp=66149192409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149192409&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-08-1657

DO - 10.1158/1078-0432.CCR-08-1657

M3 - Article

VL - 15

SP - 3416

EP - 3422

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 10

ER -