Identification of New Mechanisms of Cellular Response to Chemotherapy by Tracking Changes in Post-Translational Modifications by Ubiquitin and Ubiquitin-Like Proteins
Identification of New Mechanisms of Cellular Response to Chemotherapy by Tracking Changes in Post-Translational Modifications by Ubiquitin and Ubiquitin-Like Proteins
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DOI：
10.1021/pr401258d
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发表时间：
2014-05-01
影响因子：
4.4
通讯作者：
Soubeyran, Philippe
中科院分区：
文献类型：
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作者：
Bonacci, Thomas;Audebert, Stephane;Soubeyran, Philippe
胰腺导管腺癌(PDAC)是一种侵袭性很强的恶性肿瘤，其特点是对所有已知的抗癌治疗都有过度抵抗，这在很大程度上仍然是一种难以捉摸的现象。为了确定最初的机制，我们探索了泛素家族成员介导的翻译后修饰(PTM)的作用。尽管在不同的癌症中已经报道了这些通路的改变，但到目前为止还没有对这些类型的异常进行系统的研究。因此，我们研究了胰腺癌细胞系(MiaPaCa-2)的泛素、Nedd8和SUMO1特异性蛋白质组，并确定了标准的PDAC化疗药物吉西他滨所诱导的变化。这些PTMS图谱既包含所有三种改性剂的已知主要底物，也包含原始底物。吉西他滨治疗改变了参与各种生物学功能的蛋白质的PTM谱，一些已知的癌症相关基因，许多潜在的癌症相关基因，以及几个癌症信号网络，包括规范和非规范的WNT和PI3K/Akt/MTOR通路。其中一些改变的PTM形成了一组功能和物理上相关的蛋白质。重要的是，我们可以验证吉西他滨诱导的相关候选PTMS的变异，并且我们可以通过详细研究这些新靶点之一SNIP！的总和作用来证明这种改变的PTMS的生物学意义。
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive malignancy characterized by an excessive resistance to all known anticancer therapies, a still largely elusive phenomenon. To identify original mechanisms, we have explored the role of post-translational modifications (PTMs) mediated by members of the ubiquitin family. Although alterations of these pathways have been reported in different cancers, no methodical search for these kinds of anomalies has been performed so far. Therefore, we studied the ubiquitin-, Nedd8-, and SUMO1-specific proteomes of a pancreatic cancer cell line (MiaPaCa-2) and identified changes induced by gemcitabine, the standard PDAC's chemotherapeutic drug. These PTMs profiles contained both known major substrates of all three modifiers as well as original ones. Gemcitabine treatment altered the PTM profile of proteins involved in various biological functions, some known cancer associated genes, many potentially cancer-associated genes, and several cancer-signaling networks, including canonical and noncanonical WNT and PI3K/Akt/MTOR pathways. Some of these altered PTMs formed groups of functionally and physically associated proteins. Importantly, we could validate the gemcitabine-induced PTMs variations of relevant candidates and we could demonstrate the biological significance of such altered PTMs by studying in detail the sumoylation of SNIP!, one of these new targets.