Sequential combination of docetaxel with a SHP-1 agonist enhanced suppression of p-STAT3 signaling and apoptosis in triple negative breast cancer cells

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2017-09, Vol.95 (9), p.965-975
• Main Authors: Liu, Chun-Yu, Chen, Kuen-Feng, Chao, Tzu-I, Chu, Pei-Yi, Huang, Chun-Teng, Huang, Tzu-Ting, Yang, Hsiu-Ping, Wang, Wan-Lun, Lee, Chia-Han, Lau, Ka-Yi, Tsai, Wen-Chun, Su, Jung-Chen, Wu, Chia-Yun, Chen, Ming-Huang, Shiau, Chung-Wai, Tseng, Ling-Ming
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cell Line, Tumor; Cell lines; Cell Proliferation - drug effects; Chemotherapy; Cyclin D1; Cytotoxicity; Disease Models, Animal; Docetaxel; Drug Synergism; Ectopic expression; Female; Gene expression; Gene Expression Regulation, Neoplastic; GLP-1 receptor agonists; Growth inhibition; Human Genetics; Humans; Inhibition; Internal Medicine; Medical prognosis; Mice; Molecular Medicine; Mutants; Original Article; Phenyl Ethers - pharmacology; Phenylurea Compounds - pharmacology; Prognosis; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; SHP-1 protein; Signal Transduction - drug effects; siRNA; Stat3 protein; STAT3 Transcription Factor - metabolism; Survival; Taxoids - pharmacology; Transcription, Genetic; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - mortality; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-017-1549-x

Triple negative breast cancer (TNBC) is an aggressive cancer for which prognosis remains poor. Combination therapy is a promising strategy for enhancing treatment efficacy. Blockade of STAT3 signaling may enhance the response of cancer cells to conventional chemotherapeutic agents. Here we used a SHP-1 agonist SC-43 to dephosphorylate STAT3 thereby suppressing oncogenic STAT3 signaling and tested it in combination with docetaxel in TNBC cells. We first analyzed messenger RNA (mRNA) expression of SHP-1 gene ( PTPN6 ) in a public TNBC dataset (TCGA) and found that higher SHP-1 mRNA expression is associated with better overall survival in TNBC patients. Sequential combination of docetaxel and SC-43 in vitro showed enhanced anti-proliferation and apoptosis associated with decreased p-STAT3 and decreased STAT3-downstream effector cyclin D1 in the TNBC cell lines MDA-MB-231, MDA-MB-468, and HCC-1937. Ectopic expression of STAT3 reduced the increased cytotoxicity induced by the combination therapy. In addition, this sequential combination showed enhanced SHP-1 activity compared to SC-43 alone. Furthermore, the combination treatment-induced apoptosis was attenuated by small interfering RNA (siRNA) against SHP-1 or by ectopic expression of SHP-1 mutants that caused SC-43 to lose its SHP-1 agonist capability. Moreover, combination of docetaxel and SC-43 showed enhanced tumor growth inhibition compared to single-agent therapy in mice bearing MDA-MB-231 tumor xenografts. Our results suggest that the novel SHP-1 agonist SC-43 enhanced docetaxel-induced cytotoxicity by SHP-1 dependent STAT3 inhibition in human triple negative breast cancer cells. TNBC patients with high SHP-1 expressions show better survival. Docetaxel combined with SC-43 enhances cell apoptosis and reduces p-STAT3. SHP-1 inhibition reduces the enhanced effect of docetaxel-SC-43 combination. Docetaxel-SC-43 combination suppresses xenograft tumor growth and reduces p-STAT3. Key messages TNBC patients with high SHP-1 expressions show better survival. Docetaxel combined with SC-43 enhances cell apoptosis and reduces p-STAT3. SHP-1 inhibition reduces the enhanced effect of docetaxel-SC-43 combination. Docetaxel-SC-43 combination suppresses xenograft tumor growth and reduces p-STAT3.