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Journal of Virology, April 2007, p. 4186-4198, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02601-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cytosolic Activation of Cathepsins Mediates Parvovirus H-1-Induced Killing of Cisplatin and TRAIL-Resistant Glioma Cells{triangledown}

Matteo Di Piazza,1* Carmen Mader,1 Karsten Geletneky,2 Marta Herrero y Calle,3 Ekkehard Weber,4 Jörg Schlehofer,1 Laurent Deleu,1,{dagger} and Jean Rommelaere1,{dagger}

Infection and Cancer Program, Division F010 and INSERM Unit 701, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany,1 Department of Neurosurgery, University of Heidelberg, 69120 Heidelberg, Germany,2 Department of Neurosurgery, University Hospital of Freiburg, 79106 Freiburg, Germany,3 Institute of Physiological Chemistry, Martin Luther University Halle-Wittenberg, 06108 Halle, Germany4

Received 24 November 2006/ Accepted 30 January 2007

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.

* Corresponding author. Mailing address: German Cancer Research Center, Division F010, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany. Phone: 49-6221-424968. Fax: 49-6221-424962. E-mail: m.dipiazza{at}dkfz.de

{triangledown} Published ahead of print on 7 February 2007.

{dagger} L.D. and J.R. contributed equally to the work.

Journal of Virology, April 2007, p. 4186-4198, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02601-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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