title: Basal caspase activity promotes migration and invasiveness in glioblastoma cells.
abstract: Glioblastomas, the most malignant of all brain tumors, are characterized by cellular resistance to apoptosis and a highly invasive growth pattern. These factors contribute to the poor response of glioblastomas to radiochemotherapy and prevent their complete neurosurgical resection. However, the driving force behind the distinct motility of glioma cells is only partly understood. Here, we report that in the absence of cellular stress and proapoptotic stimuli, human glioblastoma cells exhibit a constitutive activation of caspases in vivo and in vitro. The inhibition of caspases by various peptide inhibitors decreases the migration of cells in scrape motility assays and the invasiveness of cells in spheroid assays. Similarly, specific small interfering RNA- or antisense-mediated down-regulation of caspase-3 and caspase-8 results in an inhibition of the migratory potential of glioma cells. The constitutive caspase-dependent motility of glioblastoma cells is independent of CD95 activation and it is not mediated by mitogen-activated protein/extracellular signal-regulated kinase kinase signaling. The basal caspase activity is accompanied by a constant cleavage of the motility-associated gelsolin protein, which may contribute to the caspase-mediated promotion of migration and invasiveness in glioblastoma cells. Our results suggest that the administration of low doses of caspase inhibitors that block glioma cell motility without affecting the execution of apoptotic cell death may be exploited as a novel strategy for the treatment of glioblastomas.
authors.affiliation: Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Gdynia
authors.forename: Kerstin
authors.initials: K
authors.lastname: Grund
authors.forename: Anika
authors.initials: A
authors.lastname: Eckert
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Böck
authors.forename: Benjamin
authors.initials: B
authors.lastname: Funke
authors.forename: Stephan
authors.initials: S
authors.lastname: Macher-Goeppinger
authors.forename: Sebastian
authors.initials: S
authors.lastname: Sieber
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Benedict
authors.initials: B
authors.lastname: Wiestler
authors.forename: Otmar D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
mesh_terms: D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018260:Gelsolin / Q000378:metabolism; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering; D019014:fas Receptor / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018260:Gelsolin; D034741:RNA, Small Interfering; D019014:fas Receptor; D053148:Caspase 3; D053181:Caspase 8