The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells.
- Author:
Chun Yu LIU
1
;
Tzu Ting HUANG
;
Pei Yi CHU
;
Chun Teng HUANG
;
Chia Han LEE
;
Wan Lun WANG
;
Ka Yi LAU
;
Wen Chun TSAI
;
Tzu I CHAO
;
Jung Chen SU
;
Ming Huang CHEN
;
Chung Wai SHIAU
;
Ling Ming TSENG
;
Kuen Feng CHEN
Author Information
- Publication Type:Original Article
- MeSH: Apoptosis*; Breast Neoplasms; Disease-Free Survival; Humans; Protein-Tyrosine Kinases*; RNA, Small Interfering; Triple Negative Breast Neoplasms*; Tyrosine*
- From:Experimental & Molecular Medicine 2017;49(8):e366-
- CountryRepublic of Korea
- Language:English
- 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.
