A lowered 26S proteasome activity correlates with mantle lymphoma cell lines resistance to genotoxic stress

BMC Cancer

Research Article

Fatma Ben Aissa-Fennira¹  Simon Body²  Élodie Costé²  Clémence Coudre²  Hadjer Miloudi²  Fabrice Jardin³  Pierre-Julien Viailly³  Khaoula Ben Younes⁴  Brigitte Sola⁵ 

[1] Faculté de médecine, Laboratoire de Génétique, d’Immunologie et de Pathologie humaines, Université de Tunis El Manar, Tunis, Tunisia;Normandie Univ, INSERM UMR 1245, UNIROUEN, UNICAEN, Caen, France;Normandie Univ, INSERM UMR 1245, UNIROUEN, UNICAEN, Caen, France;Département d’Hématologie Clinique, Centre de Lutte contre le Cancer Henri Becquerel, Rouen, France;Normandie Univ, INSERM UMR 1245, UNIROUEN, UNICAEN, Caen, France;Faculté de médecine, Laboratoire de Génétique, d’Immunologie et de Pathologie humaines, Université de Tunis El Manar, Tunis, Tunisia;Normandie Univ, INSERM UMR 1245, UNIROUEN, UNICAEN, Caen, France;MICAH, UFR Santé, CHU Côte de Nacre, 14032, Caen Cedex, France;

关键词: B-cell lymphoma;    Apoptosis;    Cell cycle;    Senescence;    Resistance/sensitivity;    Double-strand break;    DNA repair;    Ubiquitin ligase;    26S proteasome;    PSMB6;   

DOI  :  10.1186/s12885-017-3530-z

 received in 2017-01-09, accepted in 2017-08-03,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundMantle cell lymphoma (MCL) is a B-cell hemopathy characterized by the t(11;14) translocation and the aberrant overexpression of cyclin D1. This results in an unrestrained cell proliferation. Other genetic alterations are common in MCL cells such as SOX11 expression, mutations of ATM and/or TP53 genes, activation of the NF-κB signaling pathway and NOTCH receptors. These alterations lead to the deregulation of the apoptotic machinery and resistance to drugs. We observed that among a panel of MCL cell lines, REC1 cells were resistant towards genotoxic stress. We studied the molecular basis of this resistance.MethodsWe analyzed the cell response regarding apoptosis, senescence, cell cycle arrest, DNA damage response and finally the 26S proteasome activity following a genotoxic treatment that causes double strand DNA breaks.ResultsMCL cell lines displayed various sensitivity/resistance towards genotoxic stress and, in particular, REC1 cells did not enter apoptosis or senescence after an etoposide treatment. Moreover, the G2/M cell cycle checkpoint was deficient in REC1 cells. We observed that three main actors of apoptosis, senescence and cell cycle regulation (cyclin D1, MCL1 and CDC25A) failed to be degraded by the proteasome machinery in REC1 cells. We ruled out a default of the βTrCP E3-ubiquitine ligase but detected a lowered 26S proteasome activity in REC1 cells compared to other cell lines.ConclusionThe resistance of MCL cells to genotoxic stress correlates with a low 26S proteasome activity. This could represent a relevant biomarker for a subtype of MCL patients with a poor response to therapies and a high risk of relapse.

【 授权许可】

CC BY   
© The Author(s). 2017