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

Abstract

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.

• Authors: Chun-Yu Liu, Kuen-Feng Chen, Tzu-I Chao, Pei-Yi Chu, Chun-Teng Huang, Tzu-Ting Huang, Hsiu-Ping Yang, Wan-Lun Wang, Chia-Han Lee, Ka-Yi Lau, Wen-Chun Tsai, Jung-Chen Su, Chia-Yun Wu, Ming-Huang Chen, Chung-Wai Shiau, Ling-Ming Tseng
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 95 Issue 9 Pg. 965-975 (Sep 2017) ISSN: 1432-1440 [Electronic] Germany
• PMID: 28578456 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Phenyl Ethers
• Phenylurea Compounds
• SC-43 compound
• STAT3 Transcription Factor
• Taxoids
• Docetaxel
• Protein Tyrosine Phosphatase, Non-Receptor Type 6

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Docetaxel
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Phenyl Ethers (pharmacology)
• Phenylurea Compounds (pharmacology)
• Prognosis
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (genetics, metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Taxoids (pharmacology)
• Transcription, Genetic
• Triple Negative Breast Neoplasms (genetics, metabolism, mortality)
• Xenograft Model Antitumor Assays