title: Cytosolic activation of cathepsins mediates parvovirus H-1-induced killing of cisplatin and TRAIL-resistant glioma cells.
abstract: Gliomas are often resistant to the induction of apoptotic cell death as a result of the development of survival mechanisms during astrocyte malignant transformation. In particular, the overexpression of Bcl-2-family members interferes with apoptosis initiation by DNA-damaging agents (e.g., cisplatin) or soluble death ligands (e.g., TRAIL). Using low-passage-number cultures of glioma cells, we have shown that parvovirus H-1 is able to induce death in cells resistant to TRAIL, cisplatin, or both, even when Bcl-2 is overexpressed. Parvovirus H-1 triggers cell death through both the accumulation of lysosomal cathepsins B and L in the cytosol of infected cells and the reduction of the levels of cystatin B and C, two cathepsin inhibitors. The impairment of either of these effects protects glioma cells from the viral lytic effect. In normal human astrocytes, parvovirus H-1 fails to induce a killing mechanism. In vivo, parvovirus H-1 infection of rat glioma cells intracranially implanted into recipient animals triggers cathepsin B activation as well. This report identifies for the first time cellular effectors of the killing activity of parvovirus H-1 against malignant brain cells and opens up a therapeutic approach which circumvents their frequent resistance to other death inducers.
authors.affiliation: Infection and Cancer Program, Division F010 and INSERM Unit 701, and German Cancer Research Center, Division F010, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany. m.dipiazza@dkfz.de
authors.forename: Matteo
authors.initials: M
authors.lastname: Di Piazza
authors.forename: Carmen
authors.initials: C
authors.lastname: Mader
authors.forename: Karsten
authors.initials: K
authors.lastname: Geletneky
authors.forename: Marta
authors.initials: M
authors.lastname: Herrero Y Calle
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Weber
authors.forename: Jörg
authors.initials: J
authors.lastname: Schlehofer
authors.forename: Laurent
authors.initials: L
authors.lastname: Deleu
authors.forename: Jean
authors.initials: J
authors.lastname: Rommelaere
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000821:virology; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy / Q000821:virology; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D016923:Cell Death; D002945:Cisplatin / Q000494:pharmacology; D055313:Cystatin B; D055316:Cystatin C; D015891:Cystatins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005910:Glioma / Q000201:enzymology / Q000473:pathology* / Q000628:therapy / Q000821:virology*; D052661:H-1 parvovirus / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D050130:Oncolytic Virotherapy; D051381:Rats; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C525030:CST3 protein, human; C524994:CSTB protein, human; C525032:Cst3 protein, rat; D055316:Cystatin C; D015891:Cystatins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D055313:Cystatin B; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534280:Ctsl protein, rat; D002945:Cisplatin