title: Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer.
abstract: STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3(Tyr705) level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43-induced apoptosis and decreased p-STAT3(Tyr705) level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3(Tyr705) level. These data suggest that SC-43-induced apoptosis mediated through the loss of p-STAT3(Tyr705) was dependent on SHP-1 function. Importantly, SC-43-enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3(Tyr705) signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3(Tyr705)expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3(Tyr705) expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3(Tyr705) expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Fan
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Hao-Wei
authors.initials: HW
authors.lastname: Teng
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Program in Molecular Medicine, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Man-Hsin
authors.initials: MH
authors.lastname: Hung
authors.affiliation: Division of Colon and Rectal Surgery, Department Of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Shung-Haur
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Division of Colon and Rectal Surgery, Department Of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Jeng-Kai
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: kfchen1970@ntu.tdu.tw.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010647:Phenyl Ethers / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000008:administration & dosage; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000096:biosynthesis*; D011725:Pyridines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D010647:Phenyl Ethers; D010671:Phenylurea Compounds; D011725:Pyridines; C000608236:SC-43 compound; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C559147:regorafenib; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6