title: Functional roles of Src and Fgr in ovarian carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hye-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Nam
authors.forename: Jeong-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ju-Won
authors.initials: JW
authors.lastname: Roh
authors.forename: Masato
authors.initials: M
authors.lastname: Nishimura
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000081247:CSK Tyrosine-Protein Kinase; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan; D000077143:Docetaxel; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D043823:Taxoids / Q000494:pharmacology; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000235:genetics* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; D048271:Chitosan; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; C000631346:CSK protein, human; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases