Targeting Lyn inhibits tumor growth and metastasis in Ewing's sarcoma.
Src family tyrosine kinases (SFK) play an important role in growth and metastasis of many types of human malignancies. However, their significance in Ewing's sarcoma remains to be elucidated. The purpose of this study was to evaluate the role of Lyn, one member of the SFK, in Ewing's sarcoma growth and metastasis and to determine whether a SFK inhibitor can induce Ewing's tumor regression. Lyn was expressed and activated in TC71, A4573, and SK-ES human Ewing's sarcoma cells. Lyn expression was seen in 13 of 15 patient tumor samples, 6 of which showed Lyn activation. Specific inhibition of Lyn using small interfering RNA significantly decreased primary tumor growth and lytic activity, and also reduced lung metastases in vivo. Down-regulation of Lyn resulted in decreased invasive capacity of tumor cells in vitro. AP23994, a small-molecule SFK inhibitor, decreased Lyn kinase activity and suppressed TC71 cell growth in vitro in a dose-dependent manner. Furthermore, treatment of mice bearing s.c. TC71 tumors with AP23994 or with polyethylenimine/Lyn-small interfering RNA gene therapy resulted in reduced Lyn kinase activity and significant tumor growth suppression. EWS/FLI-1, which is translocation fusion protein associated with Ewing's sarcoma, regulated Lyn gene expression and kinase activity. These data suggest that targeting Lyn may be a new therapeutic approach in treatment of Ewing's sarcoma.
Guan
Hui
H
Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Unit 87, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Zhou
Zhichao
Z
Gallick
Gary E
GE
Jia
Shu-Fang
SF
Morales
Jaime
J
Sood
Anil K
AK
Corey
Seth J
SJ
Kleinerman
Eugenie S
ES
D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology* / Q000473:pathology*; D001862:Bone Resorption / Q000201:enzymology / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000201:enzymology* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D015820:Cadherins; D051789:Proto-Oncogene Protein c-fli-1; C086960:osteoblast cadherin; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases