Targeting Src family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model

Serkin Park, Jing Zhang, Kacy A. Phillips, John C. Araujo, Amer M. Najjar, Andrei Y. Volgin, Juri G. Gelovani, Sun Jin Kim, Zhengxin Wang, Gary E. Gallick

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

Aberrant expression and/or activity of members of the Src family of nonreceptor protein tyrosine kinases (SFK) are commonly observed in progressive stages of human tumors. In prostate cancer, two SFKs (Src and Lyn) have been specifically implicated in tumor growth and progression. However, there are no data in preclinical models demonstrating potential efficacy of Src inhibitors against prostate cancer growth and/or metastasis. In this study, we used the small molecule SFK/Abl kinase inhibitor dasatinib, currently in clinical trials for solid tumors, to examine in vitro and in vivo effects of inhibiting SFKs in prostate tumor cells. In vitro, dasatinib inhibits both Src and Lyn activity, resulting in decreased cellular proliferation, migration, and invasion. In orthotopic nude mouse models, dasatinib treatment effectively inhibits expression of activated SFKs, resulting in inhibition of both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant tumors. In primary tumors, SFK inhibition leads to decreased cellular proliferation (determined by immunohistochemistry for proliferating cell nuclear antigen). In vitro, small interfering RNA (siRNA)-mediated inhibition of Lyn affects cellular proliferation; siRNA inhibition of Src affects primarily cellular migration. Therefore, we conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer and that Src and Lyn activities affect different cellular functions required for prostate tumor growth and progression.

Original languageEnglish
Pages (from-to)3323-3333
Number of pages11
JournalCancer Research
Volume68
Issue number9
DOIs
Publication statusPublished - 2008 May 1
Externally publishedYes

Fingerprint

src-Family Kinases
Nude Mice
Prostatic Neoplasms
Lymph Nodes
Neoplasm Metastasis
Growth
Neoplasms
Cell Proliferation
Small Interfering RNA
Androgens
Prostate
Proliferating Cell Nuclear Antigen
Growth and Development
Protein-Tyrosine Kinases
Phosphotransferases
Therapeutics
Immunohistochemistry
Clinical Trials
Inhibition (Psychology)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting Src family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. / Park, Serkin; Zhang, Jing; Phillips, Kacy A.; Araujo, John C.; Najjar, Amer M.; Volgin, Andrei Y.; Gelovani, Juri G.; Kim, Sun Jin; Wang, Zhengxin; Gallick, Gary E.

In: Cancer Research, Vol. 68, No. 9, 01.05.2008, p. 3323-3333.

Research output: Contribution to journalArticle

Park, S, Zhang, J, Phillips, KA, Araujo, JC, Najjar, AM, Volgin, AY, Gelovani, JG, Kim, SJ, Wang, Z & Gallick, GE 2008, 'Targeting Src family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model', Cancer Research, vol. 68, no. 9, pp. 3323-3333. https://doi.org/10.1158/0008-5472.CAN-07-2997
Park, Serkin ; Zhang, Jing ; Phillips, Kacy A. ; Araujo, John C. ; Najjar, Amer M. ; Volgin, Andrei Y. ; Gelovani, Juri G. ; Kim, Sun Jin ; Wang, Zhengxin ; Gallick, Gary E. / Targeting Src family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. In: Cancer Research. 2008 ; Vol. 68, No. 9. pp. 3323-3333.
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