Centre de Recherche en Cancérologie de Marseille (CRCM), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, INSERM, Aix-Marseille University, Marseille, France.
Transcriptomique and Génomique Marseille Luminy (TGML), Théories et Approches de la Complexité Génomique (TAGC), INSERM, Aix-Marseille University, Marseille, France.
FASEB J. 2019 Nov;33(11):12447-12463. doi: 10.1096/fj.201901091R. Epub 2019 Sep 16.
The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is mainly due to its rapidly acquired resistance to all conventional treatments. Despite drug-specific mechanisms of resistance, none explains how these cells resist the stress induced by any kind of anticancer treatment. Activation of stress-response pathways relies on the post-translational modifications (PTMs) of involved proteins. Among all PTMs, those mediated by the ubiquitin family of proteins play a central role. Our aim was to identify alterations of ubiquitination, neddylation, and sumoylation associated with the multiresistant phenotype and demonstrate their implications in the survival of PDAC cells undergoing treatment. This approach pointed at an alteration of promyelocytic leukemia (PML) protein sumoylation associated with both gemcitabine and oxaliplatin resistance. We could show that this alteration of PML sumoylation is part of a general mechanism of drug resistance, which in addition involves the abnormal activation of NF-κB and cAMP response element binding pathways. Importantly, using patient-derived tumors and cell lines, we identified a correlation between the levels of PML expression and sumoylation and the sensitivity of tumors to anticancer treatments.-Swayden, M., Alzeeb, G., Masoud, R., Berthois, Y., Audebert, S., Camoin, L., Hannouche, L., Vachon, H., Gayet, O., Bigonnet, M., Roques, J., Silvy, F., Carrier, A., Dusetti, N., Iovanna, J. L., Soubeyran, P. PML hyposumoylation is responsible for the resistance of pancreatic cancer.
胰腺导管腺癌 (PDAC) 预后不佳，主要是因为它对所有常规治疗方法迅速产生耐药性。尽管存在药物特异性耐药机制，但没有一种机制能够解释这些细胞如何抵抗任何抗癌治疗所诱导的应激。应激反应途径的激活依赖于相关蛋白的翻译后修饰 (PTMs)。在所有 PTM 中，由泛素家族蛋白介导的 PTM 起着核心作用。我们的目的是鉴定与多药耐药表型相关的泛素化、类泛素化和 SUMO 化改变，并证明它们对接受治疗的 PDAC 细胞存活的影响。这种方法指出了与吉西他滨和奥沙利铂耐药相关的早幼粒细胞白血病 (PML) 蛋白 SUMO 化的改变。我们可以证明，这种 PML SUMO 化的改变是耐药的一般机制的一部分，该机制还涉及 NF-κB 和 cAMP 反应元件结合途径的异常激活。重要的是，通过使用患者来源的肿瘤和细胞系，我们确定了 PML 表达和 SUMO 化水平与肿瘤对癌症治疗的敏感性之间的相关性。
