PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor

Description

ORIGINAL PAPERS PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor Rosa-Ana Gonzalez-Polo1, Gabrielle Carvalho1, Thorsten Braun1, Didier Decaudin2, Claire Fabre1, Nathanael Larochette1, Jean-Luc Perfettini1, Mojgan Djavaheri-Mergny3, Ibtissam Youlyouz-Marfak4, Patrice Codogno3, Martine Raphael5, Jean Feuillard4 and Guido Kroemer*,1 1Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, 94805 Villejuif, France; 2Department of Hematology, Institut Curie, 75005 Paris, France; 3Institut Andre Lwoff , INSERM U504, 16 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France; 4Centre National de la Recherche Scientifique, UMR CNRS 6101 et Laboratoire d'Hematologie, faculte de Medicine et CHU Dupuytren, Limoges, France; 5Service d'Hematologie Biologique, U473, CHU Kremlin Bicetre, France 1-(2-Chlorophenyl-N-methylpropyl)-3-isoquinolinecarbox- amide (PK11195) is a prototypic ligand of the peripheral benzodiazepine receptor (PBR), a mitochondrial outer membrane protein. PK11195 can be used to chemosensitize tumor cells to a variety of chemotherapeutic agents, both in vitro and in vivo. PK11195 has been suggested to exert this effect via inhibition of the multiple drug resistance (MDR) pump and by direct mitochondrial effects which could be mediated by the PBR.

• cm nf


• hela cells


• low-affinity mpbr


• pbr


• co pk11195


• starvation- induced cell


• pk11195


• sirna specific


• sirna

Sujets

• Nature Publishing Group
• Shimizu
• Kroemer

Informations

• Publié par: pefav
• Nombre de lectures: 26
• Langue: English

Extrait

Oncogene (2005) 24, 7503–7513 & 2005 Nature Publishing Group All rights reserved 09509232/05 $30.00 www.nature.com/onc ORIGINAL PAPERS PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor

1 1 1 2 Rosa-Ana Gonzalez-Polo , Gabrielle Carvalho , Thorsten Braun , Didier Decaudin , 1 1 1 3 Claire Fabre , Nathanael Larochette , Jean-Luc Perfettini , Mojgan Djavaheri-Mergny , 4 3 5 4 Ibtissam Youlyouz-Marfak , Patrice Codogno , Martine Raphael , Jean Feuillard ,1 and Guido Kroemer*

1 Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue 2 3 Camille-Desmoulins, 94805 Villejuif, France; Department of Hematology, Institut Curie, 75005 Paris, France; Institut Andre´ Lwoff , 4 INSERM U504, 16 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France; Centre National de la Recherche Scientifique, 5 UMR CNRS 6101 et Laboratoire d’He´matologie, faculte´ de Me´dicine et CHU Dupuytren, Limoges, France; Service d’He´matologie Biologique, U473, CHU Kremlin Biceˆtre, France

1-(2-Chlorophenyl-N-methylpropyl)-3-isoquinolinecarbox- amide (PK11195) is a prototypic ligand of the peripheral benzodiazepine receptor (PBR), a mitochondrial outer membrane protein. PK11195 can be used to chemosensitize tumor cells to a variety of chemotherapeutic agents, bothin vitroandin vivo. PK11195 has been suggested to exert this effect via inhibition of the multiple drug resistance (MDR) pump and by direct mitochondrial effects which could be mediated by the PBR. Here, we established a model system in which PK11195 and another PBR ligand, 7-chloro-5-(4- chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin- 2-one (Ro5-4864), sensitize to nutrient depletion-induced cell death. In this MDR-independent model, PK11195 and Ro5-4864 are fully active even when the PBR is knocked down by small interfering RNA. Cells that lack PBR possess low-affinity binding sites for PK11195 and Ro5- 4864. The starvation-sensitizing effects of PK11195 are not due to a modulation of the adaptive response of starved cells, namely autophagy and NF-jB activation. Rather, it appears that the combination of PK11195 with autophagy or NF-jB inhibitors has a potent synergistic death-inducing effect. Starved cells treated withPK11195 exibhit characteristics of apoptosis, including loss of the mitochon- drial transmembrane potential, mitochondrial cytochromec release, caspase activation and chromatin condensation. Accordingly, stabilization of mitochondria by overexpres- sion of Bcl-2 or expression of the viral mitochondrial inhibitor (vMIA) from cytomegalovirus inhibits cell death induced by PK11195 plus starvation. Thus, PK11195 potently sensitizes to apoptosis via a pathway that involves mitochondria, yet does not involve the PBR. Oncogene(2005)24,7503–7513. doi:10.1038/sj.onc.1208907; published online 8 August 2005

Keywords:autophagy; caspase; Bcl-2; NF-kappaB

*Correspondence: G Kroemer; E-mail: [e-mail] Received 20 April 2005; revised 31 May 2005; accepted 7 June 2005; published online 8 August 2005

Introduction

The peripheral benzodiazepine receptor (PBR) has been suggested as a putative target for therapeutic cell death induction (Casellaset al. , 2002; Castedoet al., 2002). The PBR protein is overexpressed in some tumors, and this overexpression has a negative prognostic impact on breast cancer (Galiegueet al., 2004) and colorectal cancer (Maaseret al., 2005). In contrast, knockdown of PBR expression by an antisense construct enhances the tumorigenicity of murine cancer cell lines (Weisinger et al., 2004). Ligation of PBR with synthetic ligands such as 1-(2-chlorophenyl-N-methylpropyl)-3-isoquino- linecarboxamide (PK11195) or 7-chloro-5-(4-chlorophe- nyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5-4864) facilitates apoptosis induction in human tumor cells by a variety of chemotherapeutic agents, including doxorubicin (Hirschet al., 1998; Sutteret al., 2004), daunorubicin (Jakubikovaet al., 2002), etoposide (Decaudinet al., 2002; Okaroet al., 2002), 5-fluorour- acil, UV andg-irradiation (Okaroet al., 2002), ifosfamide (Decaudinet al., 2002), paclitaxel, docetaxel (Hirschet al., 1998; Sutteret al., 2004), colchicine (Jorda et al., 2005), arsenicals (Larochetteet al., 1999; Muscarellaet al., 2003), lonidamine (Ravagnanet al., 1999), and bortezomib (Chauhanet al., 2004). In addition, PK11195 can sensitize cells to apoptosis induction by anti-CD95 (Decaudinet al., 2002), the cytokine mda-7/interleukin-24 (Lebedevaet al., 2003), the proapoptotic second messenger ceramide (Hirsch et al., 1998) and the Bcl-2 antagonist HA14.1 (Chen et al., 2002; Sutteret al., 2004). Finally, PK11195 sensitizes acute myeloid leukemia cells to an anti-CD33 antibody conjugated to a calicheamicin toxin (gemtu- zumab ozogamicin) (Walteret al., 2004). Some of these effects have been obtainedin vivo, in mice bearing human lung cancer xenografts treated with etoposide or ifosfamide (Decaudinet al., 2002), in mice grafted with human cholangiocarcinoma carcinoma cells treated with etoposide (Okaroet al., 2002) and in mice injected