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.
BMC Cancer. 2017 Aug 10;17(1):538. doi: 10.1186/s12885-017-3530-z.
Mantle 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.
We 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.
MCL 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.
The 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.
套细胞淋巴瘤（MCL）是一种 B 细胞血液病，其特征是 t（11;14）易位和 cyclin D1 的异常过表达。这导致细胞不受控制地增殖。MCL 细胞中还存在其他遗传改变，如 SOX11 表达、ATM 和/或 TP53 基因突变、NF-κB 信号通路和 NOTCH 受体的激活。这些改变导致凋亡机制失调和对药物的耐药性。我们观察到，在一系列 MCL 细胞系中，REC1 细胞对遗传毒性应激具有抗性。我们研究了这种抗性的分子基础。
我们分析了细胞对凋亡、衰老、细胞周期阻滞、DNA 损伤反应以及随后发生双链 DNA 断裂的遗传毒性处理后的 26S 蛋白酶体活性的反应。
MCL 细胞系对遗传毒性应激表现出不同的敏感性/抗性，特别是 REC1 细胞在用依托泊苷处理后不会进入凋亡或衰老。此外，REC1 细胞中的 G2/M 细胞周期检查点缺失。我们观察到，凋亡、衰老和细胞周期调节的三个主要因子（cyclin D1、MCL1 和 CDC25A）在 REC1 细胞中不能被蛋白酶体机制降解。我们排除了 βTrCP E3 泛素连接酶的默认缺失，但与其他细胞系相比，REC1 细胞中的 26S 蛋白酶体活性降低。
MCL 细胞对遗传毒性应激的抗性与低 26S 蛋白酶体活性相关。这可能代表一种与对治疗反应差和复发风险高的 MCL 患者亚群相关的有价值的生物标志物。
