title: Obatoclax analog SC-2001 inhibits STAT3 phosphorylation through enhancing SHP-1 expression and induces apoptosis in human breast cancer cells.
abstract: Interfering oncogenic STAT3 signaling is a promising anti-cancer strategy. We examined the efficacy and drug mechanism of an obatoclax analog SC-2001, a novel STAT3 inhibitor, in human breast cancer cells. Human breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signaling pathways were assessed by western blot. In vivo efficacy of SC-2001 was tested in xenograft nude mice. SC-2001 inhibited cell growth and induced apoptosis in association with downregulation of p-STAT3 (Tyr 705) in breast cancer cells. STAT3-regulated proteins, including Mcl-1, survivin, and cyclin D1, were repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of protein tyrosine phosphatase SHP-1, a negative regulator of STAT3. Furthermore, the enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription by RFX-1. Chromatin immunoprecipitation assay revealed that SC-2001 increased the binding capacity of RFX-1 to the SHP-1 promoter. Knockdown of either RFX-1 or SHP-1 reduced SC-2001-induced apoptosis, whereas ectopic expression of RFX-1 increased SHP-1 expression and enhanced the apoptotic effect of SC-2001. Importantly, SC-2001 suppressed tumor growth in association with enhanced RFX-1 and SHP-1 expression and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. SC-2001 induced apoptosis in breast cancer cells, an effect that was mediated by RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. Our study indicates targeting STAT3 signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer.
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei, 112, Taiwan, liuchunyu_tw@yahoo.com.tw.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.forename: Mei-Huei
authors.initials: MH
authors.lastname: Ni
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.forename: Duen-Shian
authors.initials: DS
authors.lastname: Wang
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Kao
authors.forename: Man-Hsin
authors.initials: MH
authors.lastname: Hung
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics* / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011758:Pyrroles; C000605537:RFX1 protein, human; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; C000605538:Rfx1 protein, mouse; C572884:SC-2001; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6