Prohibitin (PHB) expression is associated with aggressiveness in DLBCL and flavagline-mediated inhibition of cytoplasmic PHB functions induces anti-tumor effects

Autor: Marie-Odile Jauberteau, Marine Aitamer, Agnès Olivrie, Lydie Dubanet, Armand de Gramont, Laurent Désaubry, D. Troutaud, Julie Abraham, Sabria Elderwish, Eric Raymond, Hafidha Bentayeb, Barbara Petit
Přispěvatelé: Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), CHU Limoges, Substances naturelles/chimie moléculaire, Université Louis Pasteur - Strasbourg I-Ecole européenne de chimie, polymères et matériaux [Strasbourg]-Centre National de la Recherche Scientifique (CNRS), Biochimie cellulaire : relations cycle cellulaire, cytosquelette et traduction (BCRCCCT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Unité Fonctionnelle Registre Général des Cancers du Limousin (UFRGC), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], Contrôle de l’Activation Cellulaire, Progression Tumorale et Résistance thérapeutique (CAPTuR), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges, Laboratoire de l'Informatique du Parallélisme (LIP), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
Cytoplasm
Aucun
Apoptosis
Mice
SCID
Mice
0302 clinical medicine
Annexin
immune system diseases
hemic and lymphatic diseases
Prohibitin
ComputingMilieux_MISCELLANEOUS
FL3
drug therapy
genetics
metabolism
Chemistry
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
Up-Regulation
Blot
Gene Expression Regulation
Neoplastic
ERK signaling
Oncology
030220 oncology & carcinogenesis
Female
Lymphoma
Large B-Cell
Diffuse
Signal transduction
Cell Survival
PHB
[SDV.CAN]Life Sciences [q-bio]/Cancer
administration & dosage
pharmacology
lcsh:RC254-282
03 medical and health sciences
Sex Factors
Cell Line
Tumor
Prohibitins
Animals
Humans
Protein kinase B
Benzofurans
Cell Proliferation
Research
Akt
Germinal center
Survival Analysis
Xenograft Model Antitumor Assays
Repressor Proteins
030104 developmental biology
Cell culture
DLBCL
drug effects
Cancer research
Zdroj: Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-15 (2019)
Journal of experimental & clinical cancer research
Journal of experimental & clinical cancer research, BioMed Central, 2019, 38 (1), ⟨10.1186/s13046-019-1440-4⟩
Journal of Experimental & Clinical Cancer Research : CR
ISSN: 1756-9966
DOI: 10.1186/s13046-019-1440-4⟩
Popis: Background Diffuse large B-cell lymphomas (DLBCLs) are aggressive lymphomas accounting for approximately a third of non-Hodgkin lymphomas. Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are scaffold proteins that promote mitochondria homeostasis and consequently cell survival, but biological functions of cytoplasmic PHBs remain largely unknown in DLBCL. Methods PHB expression was analyzed in 82 DLBCL biopsies and five DLBCL cell lines by immunohistochemistry (IHC) and Western blotting. Pharmacological inhibition of PHB using the synthetic flavagline FL3 was realized in vitro to gain insight PHB cellular functions. Effects of FL3 on DLBCL cell line viability, apoptosis, C-Raf-ERK–MNK–eIF4E signaling pathway and eIF4F complex formation and activity were evaluated by XTT assay, annexin V-FITC/PI dual staining and Western blotting respectively. Subcutaneous DLBCL xenograft model in SCID mice was also performed to determine in vivo FL3 effect. Results As in DLBCL cell lines, PHB1 and PHB2 were expressed in germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes. In patient samples, high PHB levels were associated with higher serum LDH (PHB1 and PHB2), IPIaa (PHB2), and Ki-67 (PHB2) expression. Higher PHB1 expression tends to be associated with shorter event-free survival (EFS) in patients, especially in male patients. FL3 induced apoptosis of DLBCL cell lines that was associated with inhibition of the ERK-MNK-eIF4E signaling pathway, including aggressive double/triple-hit DLBCL cell lines. This resulted in altered eIF4F complex formation and activity leading to a reduction of Bcl-2 and c-Myc expression levels. Moreover, FL3 strongly downregulated DLBCL cellular levels of Akt protein and AKT mRNA. FL3 antitumor activity was also confirmed in vivo in a murine xenograft model. Conclusion Our data indicate that PHB overexpression is associated with markers of tumor aggressiveness in DLBCL, and that targeting PHBs may be a therapeutic option, notably in aggressive subtypes.
Databáze: OpenAIRE
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