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首页> 外文期刊>Journal of experimental & clinical cancer research : >Ref-1 redox activity alters cancer cell metabolism in pancreatic cancer: exploiting this novel finding as a potential target
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Ref-1 redox activity alters cancer cell metabolism in pancreatic cancer: exploiting this novel finding as a potential target

机译：REF-1氧化还原活动改变胰腺癌中的癌细胞代谢：利用这部小说发现作为潜在目标

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Pancreatic cancer is a complex disease with a desmoplastic stroma, extreme hypoxia, and inherent resistance to therapy. Understanding the signaling and adaptive response of such an aggressive cancer is key to making advances in therapeutic efficacy. Redox factor-1 (Ref-1), a redox signaling protein, regulates the conversion of several transcription factors (TFs), including HIF-1α, STAT3 and NFκB from an oxidized to reduced state leading to enhancement of their DNA binding. In our previously published work, knockdown of Ref-1 under normoxia resulted in altered gene expression patterns on pathways including EIF2, protein kinase A, and mTOR. In this study, single cell RNA sequencing (scRNA-seq) and proteomics were used to explore the effects of Ref-1 on metabolic pathways under hypoxia. scRNA-seq comparing pancreatic cancer cells expressing less than 20% of the Ref-1 protein was analyzed using left truncated mixture Gaussian model and validated using proteomics and qRT-PCR. The identified Ref-1’s role in mitochondrial function was confirmed using mitochondrial function assays, qRT-PCR, western blotting and NADP assay. Further, the effect of Ref-1 redox function inhibition against pancreatic cancer metabolism was assayed using 3D co-culture in vitro and xenograft studies in vivo. Distinct transcriptional variation in central metabolism, cell cycle, apoptosis, immune response, and genes downstream of a series of signaling pathways and transcriptional regulatory factors were identified in Ref-1 knockdown vs Scrambled control from the scRNA-seq data. Mitochondrial DEG subsets downregulated with Ref-1 knockdown were significantly reduced following Ref-1 redox inhibition and more dramatically in combination with Devimistat in vitro. Mitochondrial function assays demonstrated that Ref-1 knockdown and Ref-1 redox signaling inhibition decreased utilization of TCA cycle substrates and slowed the growth of pancreatic cancer co-culture spheroids. In Ref-1 knockdown cells, a higher flux rate of?NADP? ?consuming reactions was observed suggesting the less availability of?NADP? ?and a higher level of oxidative stress in these cells. In vivo xenograft studies demonstrated that tumor reduction was potent with Ref-1 redox inhibitor similar to Devimistat. Ref-1 redox signaling inhibition conclusively alters cancer cell metabolism by causing TCA cycle dysfunction while also reducing the pancreatic tumor growth in vitro as well as in vivo.
机译：胰腺癌是一种复杂的疾病，具有脱氧基质，极端缺氧和治疗的固有抗性。了解这种侵略性癌症的信令和适应性响应是在治疗疗效进展的关键。氧化还原因子-1（REF-1），氧化还原信号蛋白，调节几种转录因子（TFS）的转化，包括从氧化到降低状态的HIF-1α，Stat3和NFκB，导致其DNA结合的增强。在我们以前公布的工作中，常氧的Ref-1敲低导致途径的改变的基因表达模式，包括EIF2，蛋白激酶A和MTOR。在该研究中，使用单细胞RNA测序（ScRNA-SEQ）和蛋白质组学来探讨REF-1对缺氧下代谢途径的影响。使用左截短的混合物高斯模型分析表达胰腺癌细胞的胰腺癌细胞，并使用蛋白质组学和QRT-PCR验证。使用线粒体功能测定，QRT-PCR，Western印迹和NADP测定，确认了所识别的Ref-1在线粒体功能中的作用。此外，使用在体内的体外和异种移植研究中的3D共培养研究，测定Ref-1氧化还原功能抑制对胰腺癌代谢的影响。从SCRNA-SEQ数据中鉴定了一系列信号通路和转录调节因子下游的中央代谢，细胞周期，细胞凋亡，免疫应答和基因的不同转录变异和转录调节因子的基因。在ref-1氧化还原抑制中，用REF-1敲低的线粒体DEG子集显着降低，并且在体外与Devimistat相结合，显着降低。线粒体功能测定证明，REF-1敲低和REF-1氧化还原信号抑制降低了TCA循环底物的利用率，并减慢了胰腺癌共培养型球状体的生长。在REF-1敲低细胞中，允许率较高？NADP？观察到消耗反应，表明何种可用性？NADP？ ？这些细胞中氧化胁迫较高。体内异种移植研究表明，肿瘤减少有效与类似于Devimistat的Ref-1氧化还原抑制剂。 REF-1氧化还原信号传导抑制通过引起TCA循环功能障碍，同时在体外和体内减少胰腺肿瘤生长的同时，使癌细胞代谢的变得最终改变癌细胞代谢。

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