title: MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells.
abstract: Maternal embryonic leucine-zipper kinase (MELK) shows oncogenic properties in basal-like breast cancer, a cancer subtype sharing common molecular features with high-grade serous ovarian cancer. We examined the potential of MELK as a molecular and pharmacological target for treatment of epithelial ovarian cancer (EOC).
  
  
  
  Bioinformatic analysis was performed on nine OC transcriptomic data sets totaling 1241 patients. Effects of MELK depletion by shRNA or inhibition by OTSSP167 in cell lines were assessed by colony formation and MTT (proliferation) assays, Western blotting (apoptosis), and flow cytometry (cell cycle analysis).
  
  
  
  Elevated MELK expression was correlated with histological grading (n=6 data sets, p<0.05) and progression-free survival (HR 5.73, p<0.01) in OC patients and elevated MELK expression in other cancers with disease-free survival (n=3495, HR 1.071, p<0.001). Inhibition or depletion of MELK reduced cell proliferation and anchorage-dependent and -independent growth in various OC cell lines through a G2/M cell cycle arrest, eventually resulting in apoptosis. OTSSP167 retained its cytotoxicity in Cisplatin- and Paclitaxel-resistant IGROV1 and TYK-nu OC cells and sensitized OVCAR8 cells to Carboplatin but not Paclitaxel.
  
  
  
  MELK inhibition by OTSSP167 may thus present a strategy to treat patients with aggressive, progressive, and recurrent ovarian cancer.
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
authors.forename: Reto S
authors.initials: RS
authors.lastname: Kohler
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
authors.forename: Henriette
authors.initials: H
authors.lastname: Kettelhack
authors.affiliation: Hospital for Women, Department of Gynecology and Gynecological Oncology, University Hospital Basel, University of Basel, Switzerland.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Knipprath-Mészaros
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
authors.forename: André
authors.initials: A
authors.lastname: Fedier
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schoetzau
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Glyco-Oncology, Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland. Electronic address: francis.jacob@unibas.ch.
authors.forename: Francis
authors.initials: F
authors.lastname: Jacob
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Hospital for Women, Department of Gynecology and Gynecological Oncology, University Hospital Basel, University of Basel, Switzerland. Electronic address: viola.heinzelmann@usb.ch.
authors.forename: Viola
authors.initials: V
authors.lastname: Heinzelmann-Schwarz
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D018613:Microscopy, Confocal; D009287:Naphthyridines / Q000494:pharmacology; D060787:Neoplasm Grading; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
chemical_list: C585656:1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Apoptosis; Disease outcome; Drug resistance; Oncogenic growth; TCGA