Tchoghandjian A, Soubéran A, Tabouret E, Colin C, Denicolaï E, Jiguet-Jiglaire C, El-Battari A, Villard C, Baeza-Kallee N, Figarella-Branger D
Aix-Marseille University, Inserm, CRO2 UMR_S 911, Marseille, France.
AP-HM, Timone Hospital, Department of Neuro-Oncology, Marseille, France.
Cell Death Dis. 2016 Aug 4;7(8):e2325. doi: 10.1038/cddis.2016.214.
Glioblastomas (GBMs) are the most aggressive primary brain tumors in adult and remain a therapeutic challenge. Targeting key apoptosis regulators with the ultimate aim to restore apoptosis in tumor cells could be an interesting therapeutic strategy. The inhibitors of apoptosis proteins (IAPs) are regulators of cell death and represent attractive targets, especially because they can be antagonized by SMAC mimetics. In this study, we first investigated the expression of cIAP1, cIAP2, XIAP and ML-IAP in human GBM samples and in four different cell lines. We showed that all GBM samples and GBM cell lines expressed all these IAPs, although the expression of each IAP varied from one case to another. We then showed that high level of ML-IAP predicted worse progression-free survival and overall survival in both univariate and multivariate analyses in two independent cohorts of 58 and 43 primary human GBMs. We then used GDC-0152, a SMAC mimetic that antagonizes these IAPs and confirmed that GDC-0152 treatment in vitro decreased IAPs in all the cell lines studied. It affected cell line viability and triggered apoptosis, although the effect was higher in U87MG and GL261 than in GBM6 and GBM9 cell lines. In vivo, GDC-0152 effect on U87MG orthotopic xenografts was dose dependent; it postponed tumor formation and slowed down tumor growth, significantly improving survival of GBM-bearing mice. This study revealed for the first time that ML-IAP protein expression correlates with GBM patient survival and that its antagonist GDC-0152 improves outcome in xenografted mouse.
胶质母细胞瘤（GBM）是成人中最具侵袭性的原发性脑肿瘤，仍然是一个治疗难题。以恢复肿瘤细胞凋亡为最终目标靶向关键凋亡调节因子可能是一种有趣的治疗策略。凋亡抑制蛋白（IAP）是细胞死亡的调节因子，是有吸引力的靶点，特别是因为它们可被SMAC模拟物拮抗。在本研究中，我们首先调查了人GBM样本和四种不同细胞系中cIAP1、cIAP2、XIAP和ML-IAP的表达。我们发现所有GBM样本和GBM细胞系均表达所有这些IAP，尽管每种IAP的表达因病例而异。然后我们发现，在两个分别有58例和43例原发性人GBM的独立队列中，单变量和多变量分析均显示，高水平的ML-IAP预示着无进展生存期和总生存期更差。然后我们使用了一种拮抗这些IAP的SMAC模拟物GDC-0152，并证实体外GDC-0152处理可降低所有研究细胞系中的IAP。它影响细胞系活力并引发凋亡，尽管在U87MG和GL261中的作用比在GBM6和GBM9细胞系中更强。在体内，GDC-0152对U87MG原位异种移植物的作用呈剂量依赖性；它推迟了肿瘤形成并减缓了肿瘤生长，显著提高了荷GBM小鼠的生存率。这项研究首次揭示，ML-IAP蛋白表达与GBM患者生存率相关，并且其拮抗剂GDC-0152可改善异种移植小鼠的预后。
