title: Inhibiting p21-Activated Kinase Induces Cell Death in Vestibular Schwannoma and Meningioma via Mitotic Catastrophe.
abstract: p21-activated kinase (PAK) regulates signaling pathways that promote cell survival and proliferation; therefore, pharmacological inhibition of PAK will induce cell death in vestibular schwannomas (VS) and meningiomas.
  
  
  
  All VS and many meningiomas result from loss of the neurofibromatosis type 2 (NF2) gene product merlin, with ensuing PAK hyperactivation and increased cell proliferation/survival.
  
  
  
  The novel small molecule PAK inhibitors PI-8 and PI-15-tested in schwannoma and meningioma cells-perturb molecular signaling and induce cell death. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay analyzed PAK inhibitors' effect on cell viability, cell cycle, and cell death, respectively. Western blots evaluated activation and expression of cell proliferation, apoptotic, and mitotic catastrophe markers. Light microscopy evaluated cell morphology, and immunocytochemistry analyzed cellular localization of phospho-Merlin and autophagy-related protein.
  
  
  
  Treatment with PI-8 and PI-15 decreased cell viability at 0.65 to 3.7 μM 50% inhibitory concentration (IC50) in schwannoma and meningioma cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling and immunocytochemistry studies show that PI-8 and PI-15 induce mitotic catastrophe but not apoptosis in HEI193 cells while in BenMen1 cells, PI-8 induces autophagy and mitotic catastrophe. PI-15 induces apoptosis in BenMen1 cells. PAK inhibitor treated cells show phospho-Merlin localized to over-duplicated centrosomes of dividing cells, multiple enlarged nuclei, and misaligned/missegregated chromosomes-markers for mitotic catastrophe. Increased autophagy-related protein levels in the nucleus confirmed this cell death type. PI-8 and PI-15 inhibits PAK in both cell lines. However, only PI-15 inhibits v-akt murine thymoma viral oncogene homolog in BenMen1 cells.
  
  
  
  PAK inhibitors induce cell death in schwannoma and meningioma cells, at least in part, by mitotic catastrophe.
authors.affiliation: *Ear Institute University of Arizona †Department of Otolaryngology-Head & Neck Surgery, College of Medicine University of Arizona ‡Arizona Cancer Center §BIO5 Institute University of Arizona, Arizona.
authors.forename: Melania Ester
authors.initials: ME
authors.lastname: Mercado-Pimentel
authors.forename: Craig
authors.initials: C
authors.lastname: Miller
authors.forename: Daniela N
authors.initials: DN
authors.lastname: Rolph
authors.forename: Edrick F
authors.initials: EF
authors.lastname: Villalobos
authors.forename: Allison M
authors.initials: AM
authors.lastname: Dunn
authors.forename: Prithvi M
authors.initials: PM
authors.lastname: Mohan
authors.forename: Suzu
authors.initials: S
authors.lastname: Igarashi
authors.forename: Xiangdang
authors.initials: X
authors.lastname: Liu
authors.forename: Macken
authors.initials: M
authors.lastname: Yrun-Duffy
authors.forename: Neal K
authors.initials: NK
authors.lastname: Patel
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Read
authors.forename: Ross H
authors.initials: RH
authors.lastname: Francis
authors.forename: Adelina Isabella
authors.initials: AI
authors.lastname: Lane
authors.forename: Swaroop
authors.initials: S
authors.lastname: Murugesh
authors.forename: Abraham
authors.initials: A
authors.lastname: Jacob
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D008577:Meningeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D008579:Meningioma / Q000378:metabolism / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects; D009464:Neuroma, Acoustic / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054462:p21-Activated Kinases