title: A novel small molecular STAT3 inhibitor, LY5, inhibits cell viability, cell migration, and angiogenesis in medulloblastoma cells.
abstract: Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated and could contribute to tumorigenesis of medulloblastoma. Numerous studies have demonstrated that inhibition of the persistent STAT3 signaling pathway results in decreased proliferation and increased apoptosis in human cancer cells, indicating that STAT3 is a viable molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable small molecule, named LY5, to target STAT3 in medulloblastoma cells. LY5 inhibited persistent STAT3 phosphorylation and induced apoptosis in human medulloblastoma cell lines expressing constitutive STAT3 phosphorylation. The inhibition of STAT3 signaling by LY5 was confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, bcl-XL, survivin, and micro-RNA-21. LY5 also inhibited the induction of STAT3 phosphorylation by interleukin-6 (IL-6), insulin-like growth factor (IGF)-1, IGF-2, and leukemia inhibitory factor in medulloblastoma cells, but did not inhibit STAT1 and STAT5 phosphorylation stimulated by interferon-γ (IFN-γ) and EGF, respectively. In addition, LY5 blocked the STAT3 nuclear localization induced by IL-6, but did not block STAT1 and STAT5 nuclear translocation mediated by IFN-γ and EGF, respectively. A combination of LY5 with cisplatin or x-ray radiation also showed more potent effects than single treatment alone in the inhibition of cell viability in human medulloblastoma cells. Furthermore, LY5 demonstrated a potent inhibitory activity on cell migration and angiogenesis. Taken together, these findings indicate LY5 inhibits persistent and inducible STAT3 phosphorylation and suggest that LY5 is a promising therapeutic drug candidate for medulloblastoma by inhibiting persistent STAT3 signaling.
authors.affiliation: From the Department of Pediatrics, College of Medicine, Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio 43205 and.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.affiliation: From the Department of Pediatrics, College of Medicine, Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio 43205 and.
authors.forename: Hemant Kumar
authors.initials: HK
authors.lastname: Bid
authors.affiliation: From the Department of Pediatrics, College of Medicine, Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio 43205 and.
authors.forename: David
authors.initials: D
authors.lastname: Jou
authors.affiliation: From the Department of Pediatrics, College of Medicine, Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio 43205 and.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: the Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Wenying
authors.initials: W
authors.lastname: Yu
authors.affiliation: the Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.affiliation: From the Department of Pediatrics, College of Medicine, Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio 43205 and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: From the Department of Pediatrics, College of Medicine, Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio 43205 and lin.674@osu.edu.
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008527:Medulloblastoma / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077022:Survivin; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C582914:5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide; D000631:Aminopyridines; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D056741:Cyclin D; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D000077022:Survivin; D051020:bcl-X Protein; D002945:Cisplatin
keywords: Apoptosis; Cancer Therapy; Interleukin 6 (IL-6); Medulloblastoma; STAT3