title: NPM1 histone chaperone is upregulated in glioblastoma to promote cell survival and maintain nucleolar shape.
abstract: Glioblastoma (grade IV glioma) is the most common and aggressive adult brain tumor. A better understanding of the biology of glioblastoma cells is crucial to identify molecular targets stimulating cell death. NPM1 (nucleophosmin) is a multifunctional chaperone that plays an important role in cancer development. Herein, NPM1 was analyzed by immunohistochemistry in human astrocytic gliomas. NPM1 was detected in all tumors but with a significantly higher staining intensity in grade IV than in low grade tumors. Depletion of NPM1 had only modest effects on the viability of U251MG, U1242MG, and U343MGa Cl2:6 glioma cells, despite alterations in nucleolar morphology. Glioma cell cultures depleted of NPM1 exposed to micromolar levels of actinomycin D were more prone to cell death (apoptosis) compared to cultures retaining NPM1. We had previously found that NPM1 binds to linker histone H1.5. Here we could show that silencing of H1.5 triggered glioma cell apoptosis as evidenced by a marked increase in both the numbers of cleaved caspase-3(+) cells and in the amounts of cleaved PARP. Enforced expression of NPM1 suppressed apoptosis in H1.5 depleted glioma cells. Although our studies would suggest little effectiveness of targeting NPM1 alone there could be potential using it as a combination treatment.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, CCK R8:05, Karolinska University Hospital in Solna, SE-17176 Stockholm, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Holmberg Olausson
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, CCK R8:05, Karolinska University Hospital in Solna, SE-17176 Stockholm, Sweden.|Department of Neuroscience, Neurology, Uppsala University, Uppsala University Hospital, SE-75185 Uppsala.
authors.forename: Tamador
authors.initials: T
authors.lastname: Elsir
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, CCK R8:05, Karolinska University Hospital in Solna, SE-17176 Stockholm, Sweden.
authors.forename: Kaveh
authors.initials: K
authors.lastname: Moazemi Goudarzi
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, CCK R8:05, Karolinska University Hospital in Solna, SE-17176 Stockholm, Sweden.
authors.forename: Monica
authors.initials: M
authors.lastname: Nistér
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, CCK R8:05, Karolinska University Hospital in Solna, SE-17176 Stockholm, Sweden.|Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 21, Stockholm, Sweden.
authors.forename: Mikael S
authors.initials: MS
authors.lastname: Lindström
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D018345:Mice, Knockout; D060787:Neoplasm Grading; D058953:Neural Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D011379:Prognosis; D021381:Protein Transport
chemical_list: D056488:Histone Chaperones; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D003609:Dactinomycin