title: Maternal embryonic leucine zipper kinase: key kinase for stem cell phenotype in glioma and other cancers.
abstract: Maternal embryonic leucine zipper kinase (MELK) is a member of the snf1/AMPK family of protein serine/threonine kinases that has recently gained significant attention in the stem cell and cancer biology field. Recent studies suggest that activation of this kinase is tightly associated with extended survival and accelerated proliferation of cancer stem cells (CSC) in various organs. Overexpression of MELK has been noted in various cancers, including colon, breast, ovaries, pancreas, prostate, and brain, making the inhibition of MELK an attractive therapeutic strategy for a variety of cancers. In the experimental cancer models, depletion of MELK by RNA interference or small molecule inhibitors induces apoptotic cell death of CSCs derived from glioblastoma multiforme and breast cancer, both in vitro and in vivo. Mechanism of action of MELK includes, yet may not be restricted to, direct binding and activation of the oncogenic transcription factors c-JUN and FOXM1 in cancer cells but not in the normal counterparts. Following these preclinical studies, the phase I clinical trial for advanced cancers with OTSSP167 started in 2013, as the first-in-class MELK inhibitor. This review summarizes the current molecular understanding of MELK and the recent preclinical studies about MELK as a cancer therapeutic target.
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Ganguly
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hong
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Luke G F
authors.initials: LG
authors.lastname: Smith
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CaliforniaAuthors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CaliforniaAuthors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CaliforniaAuthors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Harley I
authors.initials: HI
authors.lastname: Kornblum
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CaliforniaAuthors' Affiliations: Department of Neurological Surgery; The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Departments of Psychiatry, Pharmacology, and Pediatrics; and The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California Ichiro.nakano@osumc.edu.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009287:Naphthyridines / Q000627:therapeutic use; D014411:Neoplastic Stem Cells / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034622:RNA Interference; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C585656:1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone; D009287:Naphthyridines; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases