The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells.

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.

• Authors: Chun-Yu Liu, 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
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 49 Issue 8 Pg. e366 (08 11 2017) ISSN: 2092-6413 [Electronic] United States
• PMID: 28798401 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Protein Kinase Inhibitors
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• Protein-Tyrosine Kinases
• PTPN6 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 6
• nintedanib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Indoles (pharmacology, therapeutic use)
• Kaplan-Meier Estimate
• Mice
• Mice, Inbred BALB C
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (genetics, metabolism)
• Protein-Tyrosine Kinases (metabolism)
• RNA, Small Interfering (genetics, metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Triple Negative Breast Neoplasms (drug therapy)
• Xenograft Model Antitumor Assays