ArticleOtology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology2017
Inhibiting p21-Activated Kinase Induces Cell Death in Vestibular Schwannoma and Meningioma via Mitotic Catastrophe.
Article in Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 9 citations in OpenAlex.
- Modeling meningioma in vitro in the omics era.Human cell · 2026Review
- The tumour immune microenvironment is enriched but suppressed in vestibular schwannoma compared to meningioma: therapeutic implications for NF2-related schwannomatosis.Acta neuropathologica communications · 2025Article
- CAP superfamily proteins in human: a new target for cancer therapy.Medical oncology (Northwood, London, England) · 2024Review
- Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis.Oncogene · 2024Article
- Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma.PloS one · 2024Article
- PAK4-relevant proliferation reduced by cell autophagy via p53/mTOR/p-AKT signaling.Translational cancer research · 2023Article
- Potential Molecular Biomarkers of Vestibular Schwannoma Growth: Progress and Prospects.Frontiers in oncology · 2021Review
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15 authors at 1 institution in 1 country.
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Abstract
hypothesisp21-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.
backgroundAll 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.
methodsThe 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.
resultsTreatment 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.
conclusionPAK inhibitors induce cell death in schwannoma and meningioma cells, at least in part, by mitotic catastrophe.
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