Cyclin G-Associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking

Michiro Susa, Edwin Choy, Xianzhe Liu, Joseph Schwab, Francis J. Hornicek, Henry Mankin, Zhenfeng Duan

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Osteosarcoma is the most frequent primary malignant bone tumor among the children. The advent of neoadjuvant chemotherapy significantly improved the prognosis of patients with osteosarcoma in the 1980s, but it has since plateaued in the past decades. Recently, one of the most researched areas in sarcoma treatment is tyrosine kinases. Here, we describe research on a serine/threonine kinase, cyclin G-associated kinase (GAK), which has not been reported in osteosarcoma previously. In this study, a lentiviral based human shRNA library was utilized to screen for kinases in KHOS and U-2OS osteosarcoma cells. The expression of GAK was examined in osteosarcoma and the effect on cell proliferation was analyzed by GAK siRNA knockdown. The level ofGAKexpression and its correlation to prognosis was analyzed in osteosarcoma tissuemicroarray. The effect of GAK depletion on insulin-like growth factor and epidermal growth factor receptor- mediated signal transduction was analyzed by Western blot. We observed that GAK was overexpressed in both osteosarcoma cell lines and tissue samples when compared with human osteoblasts. GAKknockdown by siRNA decreased cell proliferation in both drug-sensitive and multidrug-resistant osteosarcoma cell lines. Immunohistochemistry of osteosarcoma tissue microarray revealed that overexpression of GAK was associated with poor prognosis. Finally, knockdown of GAK resulted in alterations of receptor trafficking and several downstream proteins. In conclusion, our results suggest that osteosarcoma cell proliferation and survival are dependent on GAK. These findings may lead to the development of new therapeutic options for osteosarcoma.

Original languageEnglish
Pages (from-to)3342-3350
Number of pages9
JournalMolecular Cancer Therapeutics
Volume9
Issue number12
DOIs
Publication statusPublished - 2010 Dec
Externally publishedYes

Fingerprint

Cyclin G
Osteosarcoma
Phosphotransferases
Cell Proliferation
Small Interfering RNA
Cell Line
Protein-Serine-Threonine Kinases
Somatomedins
Osteoblasts
Epidermal Growth Factor Receptor
Sarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cyclin G-Associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking. / Susa, Michiro; Choy, Edwin; Liu, Xianzhe; Schwab, Joseph; Hornicek, Francis J.; Mankin, Henry; Duan, Zhenfeng.

In: Molecular Cancer Therapeutics, Vol. 9, No. 12, 12.2010, p. 3342-3350.

Research output: Contribution to journalArticle

Susa, Michiro ; Choy, Edwin ; Liu, Xianzhe ; Schwab, Joseph ; Hornicek, Francis J. ; Mankin, Henry ; Duan, Zhenfeng. / Cyclin G-Associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 12. pp. 3342-3350.
@article{c1f0679c14f547ec8a1f69ce9f591b94,
title = "Cyclin G-Associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking",
abstract = "Osteosarcoma is the most frequent primary malignant bone tumor among the children. The advent of neoadjuvant chemotherapy significantly improved the prognosis of patients with osteosarcoma in the 1980s, but it has since plateaued in the past decades. Recently, one of the most researched areas in sarcoma treatment is tyrosine kinases. Here, we describe research on a serine/threonine kinase, cyclin G-associated kinase (GAK), which has not been reported in osteosarcoma previously. In this study, a lentiviral based human shRNA library was utilized to screen for kinases in KHOS and U-2OS osteosarcoma cells. The expression of GAK was examined in osteosarcoma and the effect on cell proliferation was analyzed by GAK siRNA knockdown. The level ofGAKexpression and its correlation to prognosis was analyzed in osteosarcoma tissuemicroarray. The effect of GAK depletion on insulin-like growth factor and epidermal growth factor receptor- mediated signal transduction was analyzed by Western blot. We observed that GAK was overexpressed in both osteosarcoma cell lines and tissue samples when compared with human osteoblasts. GAKknockdown by siRNA decreased cell proliferation in both drug-sensitive and multidrug-resistant osteosarcoma cell lines. Immunohistochemistry of osteosarcoma tissue microarray revealed that overexpression of GAK was associated with poor prognosis. Finally, knockdown of GAK resulted in alterations of receptor trafficking and several downstream proteins. In conclusion, our results suggest that osteosarcoma cell proliferation and survival are dependent on GAK. These findings may lead to the development of new therapeutic options for osteosarcoma.",
author = "Michiro Susa and Edwin Choy and Xianzhe Liu and Joseph Schwab and Hornicek, {Francis J.} and Henry Mankin and Zhenfeng Duan",
year = "2010",
month = "12",
doi = "10.1158/1535-7163.MCT-10-0637",
language = "English",
volume = "9",
pages = "3342--3350",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Cyclin G-Associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking

AU - Susa, Michiro

AU - Choy, Edwin

AU - Liu, Xianzhe

AU - Schwab, Joseph

AU - Hornicek, Francis J.

AU - Mankin, Henry

AU - Duan, Zhenfeng

PY - 2010/12

Y1 - 2010/12

N2 - Osteosarcoma is the most frequent primary malignant bone tumor among the children. The advent of neoadjuvant chemotherapy significantly improved the prognosis of patients with osteosarcoma in the 1980s, but it has since plateaued in the past decades. Recently, one of the most researched areas in sarcoma treatment is tyrosine kinases. Here, we describe research on a serine/threonine kinase, cyclin G-associated kinase (GAK), which has not been reported in osteosarcoma previously. In this study, a lentiviral based human shRNA library was utilized to screen for kinases in KHOS and U-2OS osteosarcoma cells. The expression of GAK was examined in osteosarcoma and the effect on cell proliferation was analyzed by GAK siRNA knockdown. The level ofGAKexpression and its correlation to prognosis was analyzed in osteosarcoma tissuemicroarray. The effect of GAK depletion on insulin-like growth factor and epidermal growth factor receptor- mediated signal transduction was analyzed by Western blot. We observed that GAK was overexpressed in both osteosarcoma cell lines and tissue samples when compared with human osteoblasts. GAKknockdown by siRNA decreased cell proliferation in both drug-sensitive and multidrug-resistant osteosarcoma cell lines. Immunohistochemistry of osteosarcoma tissue microarray revealed that overexpression of GAK was associated with poor prognosis. Finally, knockdown of GAK resulted in alterations of receptor trafficking and several downstream proteins. In conclusion, our results suggest that osteosarcoma cell proliferation and survival are dependent on GAK. These findings may lead to the development of new therapeutic options for osteosarcoma.

AB - Osteosarcoma is the most frequent primary malignant bone tumor among the children. The advent of neoadjuvant chemotherapy significantly improved the prognosis of patients with osteosarcoma in the 1980s, but it has since plateaued in the past decades. Recently, one of the most researched areas in sarcoma treatment is tyrosine kinases. Here, we describe research on a serine/threonine kinase, cyclin G-associated kinase (GAK), which has not been reported in osteosarcoma previously. In this study, a lentiviral based human shRNA library was utilized to screen for kinases in KHOS and U-2OS osteosarcoma cells. The expression of GAK was examined in osteosarcoma and the effect on cell proliferation was analyzed by GAK siRNA knockdown. The level ofGAKexpression and its correlation to prognosis was analyzed in osteosarcoma tissuemicroarray. The effect of GAK depletion on insulin-like growth factor and epidermal growth factor receptor- mediated signal transduction was analyzed by Western blot. We observed that GAK was overexpressed in both osteosarcoma cell lines and tissue samples when compared with human osteoblasts. GAKknockdown by siRNA decreased cell proliferation in both drug-sensitive and multidrug-resistant osteosarcoma cell lines. Immunohistochemistry of osteosarcoma tissue microarray revealed that overexpression of GAK was associated with poor prognosis. Finally, knockdown of GAK resulted in alterations of receptor trafficking and several downstream proteins. In conclusion, our results suggest that osteosarcoma cell proliferation and survival are dependent on GAK. These findings may lead to the development of new therapeutic options for osteosarcoma.

UR - http://www.scopus.com/inward/record.url?scp=78650473271&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650473271&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-10-0637

DO - 10.1158/1535-7163.MCT-10-0637

M3 - Article

VL - 9

SP - 3342

EP - 3350

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 12

ER -