1. Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin's lymphoma B cells
- Author
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Anne Sophie Gallouet, Najoua Lalaoui, Guillaume Jacquemin, Thierry Guillaudeux, Elisabetta Iessi, Alexandre Morizot, Olivier Micheau, Aymeric Morlé, Carmen Garrido, Virginie Granci, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, This work was supported by grants of the Conseil Regional de Bourgogne, the INCa (Institut National du Cancer), Cancéropôle Grand-Est, ANR (Agence Nationale de la Recherche, ANR- 07-PCV-0031), and the European Community (ApopTrain Marie Curie RTN). GJ and VG were supported by fellowships from the Ligue Nationale contre le Cancer and the INCa., ANR-07-PCVI-0031,ApoMULTI-LIB,A multivalent peptide library approach to identify functional TRAIL mimetics(2007), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), ANR-07-PCVI-0031,PCVI,A multivalent peptide library approach to identify functional TRAIL mimetics ( 2007 ), Micheau, Olivier, Physique et chimie du vivant - A multivalent peptide library approach to identify functional TRAIL mimetics - - ApoMULTI-LIB2007 - ANR-07-PCVI-0031 - PCVI - VALID, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
- Subjects
p53 ,MESH: Signal Transduction ,MESH: Cell Death ,medicine.medical_treatment ,Follicular lymphoma ,TRAIL ,Antioxidants ,Inhibitor of Apoptosis Proteins ,MESH : Proto-Oncogene Proteins c-bcl-2 ,quercetin ,TNF-Related Apoptosis-Inducing Ligand ,MESH : TNF-Related Apoptosis-Inducing Ligand ,0302 clinical medicine ,MESH : Lymphoma, B-Cell ,immune system diseases ,hemic and lymphatic diseases ,bax ,MESH: Up-Regulation ,MESH : Inhibitor of Apoptosis Proteins ,Caspase 10 ,MESH: Tumor Suppressor Protein p53 ,MESH : Up-Regulation ,0303 health sciences ,Cell Death ,apoptosis ,Hematology ,MESH: Drug Resistance, Neoplasm ,Mitochondria ,Up-Regulation ,3. Good health ,Cytokine ,MESH : Drug Resistance, Neoplasm ,Proto-Oncogene Proteins c-bcl-2 ,caspases ,030220 oncology & carcinogenesis ,MESH : Quercetin ,MESH : Antioxidants ,MESH : Mitochondria ,MESH: Quercetin ,MESH: TNF-Related Apoptosis-Inducing Ligand ,Signal Transduction ,Death Domain Receptor Signaling Adaptor Proteins ,Programmed cell death ,Lymphoma, B-Cell ,MESH: Cell Line, Tumor ,MESH: Mitochondria ,Biology ,survivin ,03 medical and health sciences ,Downregulation and upregulation ,follicular lymphoma ,Cell Line, Tumor ,Survivin ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,MESH: Lymphoma, B-Cell ,MESH : Signal Transduction ,MESH: Caspase 10 ,diffused large B cell lymphoma ,MESH: Humans ,MESH : Cell Line, Tumor ,MESH: Apoptosis ,MESH : Humans ,MESH: Antioxidants ,MESH: Inhibitor of Apoptosis Proteins ,Mcl-1 ,Original Articles ,medicine.disease ,Lymphoma ,Non-Hodgkin's lymphoma ,MESH : Tumor Suppressor Protein p53 ,proteasome ,MESH: Proto-Oncogene Proteins c-bcl-2 ,Drug Resistance, Neoplasm ,Apoptosis ,MESH : Caspase 10 ,MESH : Cell Death ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,Tumor Suppressor Protein p53 ,MESH : Apoptosis ,MESH : Death Domain Receptor Signaling Adaptor Proteins ,MESH: Death Domain Receptor Signaling Adaptor Proteins - Abstract
International audience; BACKGROUND: Non-Hodgkin's B-cell lymphomas account for approximately 70% of B-cell lymphomas. While its incidence is dramatically increasing worldwide, the disease is still associated with high morbidity due to ineffectiveness of conventional therapies, creating an urgent need for novel therapeutic approaches. Unconventional compounds, including polyphenols and the cytokine TRAIL, are being extensively studied for their capacity to restore apoptosis in a large number of tumors, including lymphomas. DESIGN AND METHODS: Molecular mechanisms of TRAIL-resistance and reactivation of the apoptotic machinery by quercetin in non-Hodgkin's lymphoma cell lines were determined by Hoescht, flow cytometry, Western blot, qPCR, by use of siRNA or pharmacological inhibitors of the mitochondrial pathway and by immunoprecipitation followed by post-translational modification analysis. RESULTS: Results demonstrate that quercetin, a natural flavonoid, restores TRAIL-induced cell death in resistant transformed follicular lymphoma B-cell lines, despite high Bcl-2 expression levels due to the chromosomal translocation t(14;18). Quercetin rescues mitochondrial activation by inducing the proteasomal degradation of Mcl-1 and by inhibiting survivin expression at the mRNA level, irrespective of p53. Restoration of the TRAIL pathway requires Bax and Bak but is independent of enhanced TRAIL DISC formation. CONCLUSIONS: We demonstrate that inactivation of survivin and Mcl-1 expression by quercetin is sufficient to restore TRAIL sensitivity in resistant non-Hodgkin's lymphoma B cells. Our results suggest, therefore, that combining quercetin with TRAIL treatments may be useful in the treatment of non-Hodgkin's lymphoma.
- Published
- 2012
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