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Functional roles of Src and Fgr in ovarian carcinoma

 Hye-Sun Kim  ;  Hee Dong Han  ;  Guillermo N. Armaiz-Pena  ;  Rebecca L. Stone  ;  Eun Ji Nam  ;  Jeong-Won Lee  ;  Mian M. K. Shahzad  ;  Alpa M. Nick  ;  Sun Joo Lee  ;  Ju-Won Roh  ;  Masato Nishimura  ;  Lingegowda S. Mangala  ;  Justin Bottsford-Miller  ;  Gary E. Gallick  ;  Gabriel Lopez-Berestein  ;  Anil K. Sood 
 CLINICAL CANCER RESEARCH, Vol.17(7) : 1713-1721, 2011 
Journal Title
Issue Date
Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chitosan ; Female ; Humans ; Ki-67 Antigen/metabolism ; Mice ; Mice, Nude ; Nanoparticles ; Neoplasm Transplantation ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology* ; Ovarian Neoplasms/therapy ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Protein-Tyrosine Kinases/genetics* ; Protein-Tyrosine Kinases/physiology ; Proto-Oncogene Proteins/genetics* ; Proto-Oncogene Proteins/physiology ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/genetics* ; Taxoids/pharmacology ; Transplantation, Heterologous ; src-Family Kinases/genetics* ; src-Family Kinases/physiology
Src ; Fgr ; ovarian cancer ; chitosan nanoparticles ; siRNA
PURPOSE: Src is an attractive target because it is overexpressed in a number of malignancies, including ovarian cancer. However, the effect of Src silencing on other Src family kinases (SFKs) is not known. We hypothesized that other SFK members could compensate for the lack of Src activity.

EXPERIMENTAL DESIGN: Cell viability after either Src or Fgr silencing was examined in ovarian cancer cell lines by MTT assay. Expression of SFKs after Src silencing in ovarian cancer cells was examined by real-time reverse transcriptase (RT)-PCR. Therapeutic effect of in vivo Src and/or Fgr silencing was examined using siRNA incorporated into chitosan nanoparticles (siRNA/CH-NP). Microvessel density, cell proliferation, and apoptosis markers were determined by immunohistochemical staining in ovarian tumor tissues.

RESULTS: Src silencing enhanced cytotoxicity of docetaxel in both SKOV3ip1 and HeyA8 cells. In addition, Src silencing using siRNA/CH-NP in combination with docetaxel resulted in significant inhibition of tumor growth compared with control siRNA/CH-NP (81.8% reduction in SKOV3ip1, P = 0.017; 84.3% reduction in HeyA8, P < 0.005). These effects were mediated by decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Next, we assessed the effects of Src silencing on other SFK members in ovarian cancer cell lines. Src silencing resulted in significantly increased Fgr levels. Dual Src and Fgr silencing in vitro resulted in increased apoptosis that was mediated by increased caspase and AKT activity. In addition, dual silencing of Src and Fgr in vivo using siRNA/CH-NP resulted in the greatest reduction in tumor growth compared with silencing of either Src or Fgr alone in the HeyA8 model (68.8%, P < 0.05).

CONCLUSIONS: This study demonstrates that, in addition to Src, Fgr plays a biologically significant role in ovarian cancer growth and might represent an important target.
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1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Nam, Eun Ji(남은지) ORCID logo https://orcid.org/0000-0003-0189-3560
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