Exp Mol Med.
2017 Aug;49(8):e366. 10.1038/emm.2017.114.
The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells
- Affiliations
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- 1Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan. lmtseng@vghtpe.gov.tw
- 2Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
- 3School of Medicine, National Yang-Ming University, Taipei, Taiwan.
- 4Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan.
- 5School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
- 6Division of Hematology & Oncology, Department of Medicine, Yang-Ming Branch of Taipei City Hospital, Taipei, Taiwan.
- 7Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua City, Taiwan.
- 8Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
- 9Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
- 10Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. kfchen1970@ntu.edu.tw
- 11National Taiwan University College of Medicine, Taipei, Taiwan.
- KMID: 2389294
- DOI: http://doi.org/10.1038/emm.2017.114
Abstract
- Triple-negative breast cancer (TNBC) remains difficult to treat and urgently needs new therapeutic options. Nintedanib, a multikinase inhibitor, has exhibited efficacy in early clinical trials for HER2-negative breast cancer. In this study, we examined a new molecular mechanism of nintedanib in TNBC. The results demonstrated that nintedanib enhanced TNBC cell apoptosis, which was accompanied by a reduction of p-STAT3 and its downstream proteins. STAT3 overexpression suppressed nintedanib-mediated apoptosis and further increased the activity of purified SHP-1 protein. Moreover, treatment with either a specific inhibitor of SHP-1 or SHP-1-targeted siRNA reduced the apoptotic effects of nintedanib, which validates the role of SHP-1 in nintedanib-mediated apoptosis. Furthermore, nintedanib-induced apoptosis was attenuated in TNBC cells expressing SHP-1 mutants with constantly open conformations, suggesting that the autoinhibitory mechanism of SHP-1 attenuated the effects of nintedanib. Importantly, nintedanib significantly inhibited tumor growth via the SHP-1/p-STAT3 pathway. Clinically, SHP-1 levels were downregulated, whereas p-STAT3 was upregulated in tumor tissues, and SHP-1 transcripts were associated with improved disease-free survival in TNBC patients. Our findings revealed that nintedanib induces TNBC apoptosis by acting as a SHP-1 agonist, suggesting that targeting STAT3 by enhancing SHP-1 expression could be a viable therapeutic strategy against TNBC.
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