title: Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway.
abstract: Glioblastoma multiforme (GBM) is a devastating disease, and the current therapies have only palliative effect. Evidence is mounting to indicate that brain tumor stem cells (BTSCs) are a minority of tumor cells that are responsible for cancer initiation, propagation, and maintenance. Therapies that fail to eradicate BTSCs may ultimately lead to regrowth of residual BTSCs. However, BTSCs are relatively resistant to the current treatments. Development of novel therapeutic strategies that effectively eradicate BTSC are, therefore, essential. In a previous study, we used patient-derived GBM sphere cells (stemlike GBM cells) to enrich for BTSC and identified maternal embryonic leucine-zipper kinase (MELK) as a key regulator of survival of stemlike GBM cells in vitro. Here, we demonstrate that a thiazole antibiotic, siomycin A, potently reduced MELK expression and inhibited tumor growth in vivo. Treatment of stemlike GBM cells with siomycin A resulted in arrested self-renewal, decreased invasion, and induced apoptosis but had little effect on growth of the nonstem cells of matched tumors or normal neural stem/progenitor cells. MELK overexpression partially rescued the phenotype of siomycin A-treated stemlike GBM cells. In vivo, siomycin A pretreatment abraded the sizes of stemlike GBM cell-derived tumors in immunodeficient mice. Treatment with siomycin A of mice harboring intracranial tumors significantly prolonged their survival period compared with the control mice. Together, this study may be the first model to partially target stemlike GBM cells through a MELK-mediated pathway with siomycin A to pave the way for effective treatment of GBM.
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. ichiro.nakano@osumc.edu
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.forename: Kaushal
authors.initials: K
authors.lastname: Joshi
authors.forename: Koppany
authors.initials: K
authors.lastname: Visnyei
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Momoko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Diana
authors.initials: D
authors.lastname: Lam
authors.forename: Eric
authors.initials: E
authors.lastname: Wexler
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Saigusa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Dan R
authors.initials: DR
authors.lastname: Laks
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.forename: Mariano
authors.initials: M
authors.lastname: Viapiano
authors.forename: Harley I
authors.initials: HI
authors.lastname: Kornblum
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D010455:Peptides; D012333:RNA, Messenger; C024711:siomycin A; C484610:MELK protein, human; C108524:Melk protein, mouse; D017346:Protein Serine-Threonine Kinases