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Targeting Lyn inhibits tumor growth and metastasis in Ewing's sarcoma
Hui Guan1, Zhichao Zhou, Gary E Gallick
1Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Unit 87, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Abstract:
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.
Insights
Targeting Lyn, a Src family tyrosine kinase (SFK), shows promise for Ewing's sarcoma. Inhibiting Lyn significantly reduced tumor growth, metastasis, and invasion, suggesting it as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Src family tyrosine kinases (SFK) are implicated in various human cancers.
- The role of SFK, specifically Lyn, in Ewing's sarcoma pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of Lyn in Ewing's sarcoma growth and metastasis.
- To assess the efficacy of SFK inhibitors in Ewing's sarcoma regression.
Main Methods:
- Assessed Lyn expression and activation in Ewing's sarcoma cell lines and patient samples.
- Utilized small interfering RNA (siRNA) to inhibit Lyn.
- Administered a small-molecule SFK inhibitor (AP23994) and gene therapy (polyethylenimine/Lyn-siRNA).
- Evaluated tumor growth, lytic activity, metastasis, and invasive capacity in vitro and in vivo.
Main Results:
- Lyn was expressed and activated in Ewing's sarcoma cells and patient tumors.
- Lyn inhibition via siRNA significantly reduced tumor growth, lytic activity, and lung metastasis.
- Down-regulation of Lyn decreased tumor cell invasiveness in vitro.
- AP23994 suppressed Lyn activity and Ewing's sarcoma cell growth.
- Both AP23994 and gene therapy suppressed tumor growth in vivo.
- EWS/FLI-1 regulated Lyn expression and activity.
Conclusions:
- Lyn plays a critical role in Ewing's sarcoma progression.
- Targeting Lyn kinase activity presents a potential therapeutic strategy for Ewing's sarcoma.
- SFK inhibitors and gene therapy targeting Lyn demonstrate efficacy in preclinical models.
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