title: Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival.
abstract: BACKGROUND
  The current therapy for glioblastoma multiforme (GBM), the most aggressive and common primary brain tumor of adults, involves surgery and a combined radiochemotherapy that controls tumor progression only for a limited time window. Therefore, the identification of new molecular targets is highly necessary. Inhibition of kinases has become a standard of clinical oncology, and thus the oncogenic kinase Pim1 might represent a promising target for improvement of GBM therapy.
  
  
  METHODS
  Expression of Pim1 and associated signaling molecules was analyzed in human GBM samples, and the potential role of this kinase in patients' prognosis was evaluated. Furthermore, we analyzed the in vivo role of Pim1 in GBM cell growth in an orthotopic mouse model and examined the consequences of Pim1 inhibition in vitro to clarify underlying pathways.
  
  
  RESULTS
  In comparison with normal brain, a strong upregulation of Pim1 was demonstrated in human GBM samples. Notably, patients with short overall survival showed a significantly higher Pim1 expression compared with GBM patients who lived longer than the median. In vitro experiments with GBM cells and analysis of patients' GBM samples suggest that Pim1 regulation is dependent on epidermal growth factor receptor. Furthermore, inhibition of Pim1 resulted in reduced cell viability accompanied by decreased cell numbers and increased apoptotic cells, as seen by elevated subG1 cell contents and caspase-3 and -9 activation, as well as modulation of several cell cycle or apoptosis regulatory proteins.
  
  
  CONCLUSIONS
  Altogether, Pim1 could be a novel therapeutic target, which should be further analyzed to improve the outcome of patients with aggressive GBM.
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Susann
authors.initials: S
authors.lastname: Herzog
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Matthias Alexander
authors.initials: MA
authors.lastname: Fink
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Kerstin
authors.initials: K
authors.lastname: Weitmann
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Claudius
authors.initials: C
authors.lastname: Friedel
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Hadlich
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Sönke
authors.initials: S
authors.lastname: Langner
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Katharina
authors.initials: K
authors.lastname: Kindermann
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Tobias
authors.initials: T
authors.lastname: Holm
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Böhm
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Eskil
authors.initials: E
authors.lastname: Eskilsson
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Markus
authors.initials: M
authors.lastname: Hildner
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Michael
authors.initials: M
authors.lastname: Fritsch
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Silke
authors.initials: S
authors.lastname: Vogelgesang
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Havemann
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Christoph Alexander
authors.initials: CA
authors.lastname: Ritter
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Henriette Elisabeth
authors.initials: HE
authors.lastname: Meyer zu Schwabedissen
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Bernhard
authors.initials: B
authors.lastname: Rauch
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hoffmann
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Heyo Klaus
authors.initials: HK
authors.lastname: Kroemer
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Henry
authors.initials: H
authors.lastname: Schroeder
authors.affiliation: Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
authors.forename: Sandra
authors.initials: S
authors.lastname: Bien-Möller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D002867:Chromones / Q000008:administration & dosage; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000008:administration & dosage; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011728:Pyridones / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D002867:Chromones; D009025:Morpholines; D011728:Pyridones; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C512478:EGFR protein, human; D066246:ErbB Receptors; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: epidermal growth factor receptor; glioblastoma multiforme; pim1 kinase