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The chemopreventive agent N hydroxyphenyl retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl family

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The chemopreventive agent N-(4-hydroxyphenyl)retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family Patricia Boya1,8, Maria Celia Morales1,8, Rosa-Ana Gonzalez-Polo1, Karine Andreau1, Isabelle Gourdier1, Jean-Luc Perfettini1, Nathanael Larochette1, Aurelien Deniaud2, Fanny Baran- Marszak3, Remy Fagard4, Jean Feuillard5, Aintzane Asumendi6, Martine Raphael3, Bernard Pau7, Catherine Brenner2 and Guido Kroemer*,1 1Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Villejuif, France; 2Centre National de la Recherche Scientifique FRE 2445, Universite de Versailles/St Quentin, Versailles, France; 3Service d'Hematologie Biologique, U473, CHU Kremlin Bicetre, France; 4Laboratoire de Biochimie, Hopital Avicenne, APHP and EA 3406, Universite Paris 13, Bobigny, France; 5Laboratoire d'Hematologie, CHU Dupuytren, Limoges, France; 6Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa 48940, Bizkaia, Spain; 7Centre National de la Recherche Scientifique, UMR 5094, Montpellier, France N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) is a potent chemopreventive agent whose effect has been suggested to involve apoptosis induction. 4-HPR induces a loss of the mitochondrial transmembrane potential and the mitochondrial release of cytochrome c before caspase activation.

  • hpr

  • human ebv

  • hydroxyphenylretinamide-induced mitochondrial apoptosis

  • ccrf-cem cells

  • mmp

  • hpr-induced apoptosis

  • caspase

  • cell death

  • inducing agent doxycyclin


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&2003 Nature Publishing Group
Oncogene (2003) 22, 6220–6230 All rights reserved 09509232/03 $25.00
www.nature.com/onc
The chemopreventive agentN-(4-hydroxyphenyl)retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family
1,8 1,8 1 1 Patricia Boya , Maria Celia Morales , Rosa-Ana Gonzalez-Polo , Karine Andreau , Isabelle 1 1 1 2 Gourdier,Jean-LucPerfettini,NathanaelLarochette,Aur´elienDeniaud,FannyBaran-3 4 5 6 3 7 Marszak , Remy Fagard , Jean Feuillard , Aintzane Asumendi , Martine Raphael , Bernard Pau , 2 ,1 Catherine Brenner and Guido Kroemer*
1 2 Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Villejuif, France; Centre National de la 3 Recherche Scientifique FRE 2445, Universite´ de Versailles/St Quentin, Versailles, France; Service d’He´matologie Biologique, U473, 4 CHU Kremlin Biceˆtre, France; Laboratoire de Biochimie, Hoˆpital Avicenne, APHP and EA 3406, Universite´ Paris 13, Bobigny, 5 6 France; Laboratoire d’He´matologie, CHU Dupuytren, Limoges, France; Department of Cell Biology and Histology, School of 7 Medicine and Dentistry, University of the Basque Country, Leioa 48940, Bizkaia, Spain; Centre National de la Recherche Scientifique, UMR 5094, Montpellier, France
N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) is a potent chemopreventive agent whose effect has been suggested to involve apoptosis induction. 4-HPRinduces a loss of the mitochondrial transmembrane potential and the mitochondrial release of cytochromecbefore caspase activation. Inhibition of mitochondrial membrane permea-bilization (MMP) by transfection with Bcl-2 or the Cytomegalovirus UL37 gene product vMIA prevented caspase activation and cell death. In contrast to other retinoid derivatives, 4-HPRhas no direct MMP-inducing effects when added to isolated mitochondria or when added to proteoliposomes containing the MMP-regula-tory permeability transition pore complex (PTPC). Moreover, although reactive oxygen species (ROS) over-production appears to be instrumental for 4-HPR-induced MMP and apoptosis, inhibition of the NF-jB or p53-mediated signal transduction pathways failed to modulate 4-HPR-induced apoptosis. 4-HPR was found to cause an antioxidant-inhibitable conformational change of both Bax and Bak, leading to the exposure of their N-termini and to the mitochondrial relocalization of Bax. Cells with / /a Bax Bak genotype were resistant against the 4-HPR-induced MMP, overproduction of ROS and cell death. Altogether, these data indicate that 4-HPRinduces MMP through an ROS-mediated pathway that involves the obligatory contribution of the proapopotic Bcl-2 family members Bax and/or Bak. Oncogene(2003)22,6220–6230. doi:10.1038/sj.onc.1206827
Keywords:4-hydroxyphenylretinamide; Bax; Bcl-2; cell death; chemoprevention; mitochondria
*Correspondence: G Kroemer, CNRS-UMR1599, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille Desmoulins, F-94805 Villejuif, France; E-mail: kroemer@igr.fr 8 Contributed equally to this paper Received 14 April 2003; revised 13 May 2003; accepted 21 May 2003
Introduction
N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) has potent chemopreventive and antimetastatic effects in several animal models (Greenet al., 1999; Shaker et al., 2000; Hurstinget al., 2001; Raffaghelloet al., 2003) and is currently undergoing clinical trials for the prevention of ovarian carcinoma (De Paloet al., 2002), lung carcinoma (Cai and Jones, 1998), and breast neoplasia (Leviet al., 2001; Singletaryet al., 2001). In addition, 4-HPR can exert chemotherapeutic effects and kill cancer cells in a variety ofin vitroandin vivomodels, through the induction of apoptosis (Wuet al., 2001; Fontana and Rishi, 2002). Apoptosis is mediated through two main pathways, the extrinsic (death receptor) pathway (Krammer, 2000) and the intrinsic (mitochondrial) pathway (Kroemer and Reed, 2000). The extrinsic pathway is initiated by ligation of plasma membrane death recep-tors, which results in a step-wise recruitment of adaptors and initiator caspases (in particular, caspase-8 and -10) into the death-inducing signaling complex (DISC). In some cells (type I), activation of caspase-8 may directly trigger activation of the caspase cascade (Krammer, 2000) bypassing the mitochondrial apoptotic pathway, while in other cells (type II) caspase-8 mediates apoptosis only via proteolytic processing of BID (Li et al., 1998; Letaiet al., 2002), which then, in turn triggers mitochondrial membrane permeabilization (MMP). Some chemotherapeutic agents trigger the extrinsic pathway, by upregulating death receptors (e.g. CD95) and their ligands (e.g. CD95L), either through a type I- or type II-like signaling cascade (Fulda et al., 2001). Nonetheless, most chemotherapeutic agents trigger the mitochondrial pathway (Costantiniet al., 2000), which may be induced by various stress signals (Kroemer and Reed, 2000). In most examples, che-
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