Séry Quentin, Rabé Marion, Oliver Lisa, Vallette François M, Gratas Catherine
Team 9 "Apoptosis and Tumor Progression" CRCINA-INSERM U1232, France; Faculté de Médecine, Université de Nantes, Nantes, France; LaBCT, Institut de Cancérologie de L'Ouest (ICO), St Herblain, Nantes, France.
Team 9 "Apoptosis and Tumor Progression" CRCINA-INSERM U1232, France; Faculté de Médecine, Université de Nantes, Nantes, France.
Biochem Biophys Res Commun. 2017 Dec 2;493(4):1377-1383. doi: 10.1016/j.bbrc.2017.09.162. Epub 2017 Sep 29.
Temozolomide (TMZ) is the main chemotherapeutic agent used for treating newly diagnosed Glioblastoma Multiforme (GBM), the most frequent malignant brain tumors in adults. This alkylating agent induces DNA double strand breaks (DSBs) which in turn lead to apoptosis by activating the Bcl-2 controlled mitochondrial pathway. However, GBM invariably recur as tumors become resistant to TMZ. We investigated the implication of EGFR ligands in this resistance and we found that the pro Heparin Binding Epidermal Growth Factor (proHB-EGF) expression is linked to the early response to TMZ in human glioma cell lines. However, HB-EGF does not affect apoptosis per se although its expression is associated with the degradation of Mcl-1. HB-EGF is implicated in DSBs repair as silencing of HB-EGF increased γH2AX foci half-life as well as USP9X expression, two features that could be linked to the observed effect on Mcl-1. Our data demonstrate a new role for HB-EGF in TMZ treated cell lines.
替莫唑胺（TMZ）是用于治疗新诊断的多形性胶质母细胞瘤（GBM）的主要化疗药物，GBM是成人中最常见的恶性脑肿瘤。这种烷化剂会诱导DNA双链断裂（DSB），进而通过激活Bcl-2控制的线粒体途径导致细胞凋亡。然而，由于肿瘤对TMZ产生耐药性，GBM总是会复发。我们研究了表皮生长因子受体（EGFR）配体在这种耐药性中的作用，发现前肝素结合表皮生长因子（proHB-EGF）的表达与人类胶质瘤细胞系对TMZ的早期反应有关。然而，HB-EGF本身并不影响细胞凋亡，尽管其表达与Mcl-1的降解有关。HB-EGF参与了DSB的修复，因为沉默HB-EGF会增加γH2AX病灶的半衰期以及USP9X的表达，这两个特征可能与观察到的对Mcl-1的影响有关。我们的数据证明了HB-EGF在TMZ处理的细胞系中的新作用。
