CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology of China, Chinese Academy of Sciences , Beijing 100190, China.
ACS Nano. 2015 Oct 27;9(10):10099-112. doi: 10.1021/acsnano.5b03677. Epub 2015 Sep 9.
Abraxane, an FDA-approved albumin-bound nanoparticle (NP) form of paclitaxel (PTX) to treat breast cancer and nonsmall cell lung cancer (NSCLC), has been demonstrated to be more effective than the original Taxol, the single molecule form. We have established a cell line from NSCLC A549 cells to be resistant to Abraxane. To further understand the molecular mechanisms involved in the NP drug resistance, global protein expression profiles of Abraxane sensitive (A549) and resistant cells (A549/Abr), along with the treatment of Abraxane, have been obtained by a quantitative proteomic approach. The most significantly differentially expressed proteins are associated with lipid metabolism, cell cycle, cytoskeleton, apoptosis pathways and processes, suggesting several mechanisms are working synergistically in A549 Abraxane-resistant cells. Overexpression of proteins in the lipid metabolism processes, such as E3 ubiquitin-protein ligase RNF139 (RNF139) and Hydroxymethylglutaryl-CoA synthase (HMGCS1), have not been reported previously in the study of paclitaxel resistance, suggesting possibly different mechanism between nanoparticle and single molecular drug resistance. In particular, RNF139 is one of the most up-regulated proteins in A549 Abraxane-resistant cell line, but remains no change when the resistant cells were further treated with Abraxane and down-regulated in the sensitive cells after 4 h treatment of Abraxane. This study shows the use of a proteomic strategy to understand the unique response of drug resistant cells to a nanoparticle therapeutic.
阿博莱克斯（Abraxane），一种经 FDA 批准的紫杉醇（PTX）白蛋白结合纳米颗粒（NP）制剂，用于治疗乳腺癌和非小细胞肺癌（NSCLC），已被证明比原药紫杉醇（Taxol）更有效。我们已从 NSCLC A549 细胞中建立了一株对阿博莱克斯（Abraxane）产生耐药性的细胞系。为了进一步了解 NP 耐药性相关的分子机制，我们采用定量蛋白质组学方法获得了对阿博莱克斯（Abraxane）敏感（A549）和耐药细胞（A549/Abr）的全蛋白表达谱，以及阿博莱克斯（Abraxane）处理后的表达谱。差异最显著的表达蛋白与脂质代谢、细胞周期、细胞骨架、细胞凋亡途径和过程有关，这表明在 A549 阿博莱克斯（Abraxane）耐药细胞中存在几种协同作用的机制。在脂质代谢过程中，如 E3 泛素蛋白连接酶 RNF139（RNF139）和羟甲基戊二酰辅酶 A 合酶（HMGCS1）等蛋白的过表达，以前在紫杉醇耐药性研究中尚未报道过，这表明 NP 与单分子药物耐药性之间可能存在不同的机制。特别是，RNF139 是 A549 阿博莱克斯（Abraxane）耐药细胞系中上调最显著的蛋白之一，但在耐药细胞进一步用阿博莱克斯（Abraxane）处理时没有变化，而在敏感细胞用阿博莱克斯（Abraxane）处理 4 小时后下调。本研究表明，采用蛋白质组学策略可以了解耐药细胞对纳米药物治疗的独特反应。
