Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Physiology and Pharmacology Department, Pasteur Institute of Iran, Tehran, Iran.
J Cell Biochem. 2018 Nov;119(11):9270-9283. doi: 10.1002/jcb.27196. Epub 2018 Jun 28.
Interaction between tumor and stromal cells is beginning to be decoded as a contributor to chemotherapy resistance. Here, we aim to take a system-level approach to explore a mechanism by which stromal cells induce chemoresistance in cancer cells and subsequently identify a drug that can inhibit such interaction. Using a proteomic dataset containing quantitative data on secretome of stromal cells, we performed multivariate analyses and found that bone-marrow mesenchymal stem cells (BM-MSCs) play the most protective role against chemotherapeutics. Pathway enrichment tests showed that secreted cytokines from BM-MSCs activated 4 signaling pathways including Janus kinase-signal transducer and activator of transcription, phosphatidylinositol 3-kinase-protein kinase B, and mitogen-activated protein kinase, transforming growth factor-β in cancer cells collectively leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) transcription factor activation. Based on the data from integrated Library of Integrated Network-Based Cellular Signatures (iLINCs) program, we found that among different drugs, valproic acid (VA) affected the expression of 34 genes within the identified pathways that are activated by stromal cells. Our in vitro experiments confirmed that VA inhibits NF-kB activation in cancer cells. In addition, analyzing gene expression data in patients taking oral VA showed that this drug decreased expression of antioxidant enzymes culminating in increased oxidative stress in tumor cells. These results suggest that VA confines the protective role of stromal cells by inhibiting the adaptation mechanisms toward oxidative stress which is potentiated by stromal cells. Since VA is an already prescribed drug manifesting anticancer effects, this study provides a mechanistic insight for combination of VA with chemotherapy in the clinical setting.
肿瘤细胞与基质细胞的相互作用开始被解码为导致化疗耐药的因素。在这里，我们旨在采用系统的方法来探索一种机制，即基质细胞如何诱导癌细胞产生化疗耐药性，随后确定一种可以抑制这种相互作用的药物。我们使用包含基质细胞分泌组定量数据的蛋白质组数据集，进行了多变量分析，发现骨髓间充质干细胞（BM-MSCs）在对抗化疗药物方面发挥了最具保护作用。途径富集测试表明，BM-MSCs 分泌的细胞因子激活了包括 Janus 激酶-信号转导和转录激活因子、磷脂酰肌醇 3-激酶-蛋白激酶 B 和丝裂原活化蛋白激酶、转化生长因子-β在内的 4 条信号通路，这些通路共同导致核因子κ轻链增强子的激活B 细胞（NF-κB）转录因子激活。基于集成网络细胞信号特征库（iLINCs）计划的数据，我们发现，在不同的药物中，丙戊酸（VA）影响了由基质细胞激活的鉴定途径中的 34 个基因的表达。我们的体外实验证实，VA 抑制了癌细胞中 NF-κB 的激活。此外，分析接受口服 VA 治疗的患者的基因表达数据表明，这种药物降低了抗氧化酶的表达，导致肿瘤细胞中氧化应激增加。这些结果表明，VA 通过抑制对氧化应激的适应机制来限制基质细胞的保护作用，而氧化应激是由基质细胞增强的。由于 VA 是一种已被处方的药物，表现出抗癌作用，因此这项研究为在临床环境中将 VA 与化疗联合使用提供了机制上的见解。
