The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming.One of the most important cancer hallmarks,including aerobic glycolysis(the W...The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming.One of the most important cancer hallmarks,including aerobic glycolysis(the Warburg effect),the central carbon pathway,and multiple-branch metabolic pathway remodeling,enables tumor growth,progression,and metastasis.Phosphoenolpyruvate carboxykinase1(PCK1),a key rate-limiting enzyme in gluconeogenesis,catalyzes the conversion of oxaloacetate to phosphoenolpyruvate.PCK1 expression in gluconeogenic tissues is tightly regulated during fasting.In tumor cells,PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracellular environment.Interestingly,PCK1has ananti-oncogenic role in gluconeogenic organs(the liver and kidneys),but a tumor-promoting role in cancers arising from non-gluconeogenic organs.Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways.Aberrant PCK1 expression results in the activation of oncogenic pathways,accompanied by metabolic reprogramming,to maintain tumorigenesis.In this review,we summarize the mechanisms underlying PCK1 expression and regulation,and clarify the crosstalk between aberrant PCK1 expression,metabolic rewiring,and signaling pathway activation.In addition,we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.展开更多
目的研究固醇调节元件结合蛋白1c(sterol regulatory element binding protein 1c,SREBP1c)对肠道糖异生的调控作用。方法饥饿处理C57BL/6小鼠、SREBP1c纯合敲除型(SREBP1c-KO)和同窝野生型(SREBP1c-WT)小鼠,通过qPCR、Western blot检...目的研究固醇调节元件结合蛋白1c(sterol regulatory element binding protein 1c,SREBP1c)对肠道糖异生的调控作用。方法饥饿处理C57BL/6小鼠、SREBP1c纯合敲除型(SREBP1c-KO)和同窝野生型(SREBP1c-WT)小鼠,通过qPCR、Western blot检测糖异生途径限速酶葡萄糖-6-磷酸酶(glucose-6-phosphatase catalytic,G6PC)和磷酸烯醇式丙酮酸羧激酶(phosphoenolpyruvate carboxykinase 1,PCK1)在肝脏、空肠和回肠组织中的表达水平;在肠上皮细胞CaCo-2中过表达或敲低SREBP1c,检测细胞内G6PC和PCK1表达水平。结果饥饿处理后,C57BL/6小鼠空肠、回肠组织中G6PC、PCK1和SREBP1c表达水平均显著增加(P<0.05)。SREBP1c基因敲除后,小鼠空肠、回肠组织中由饥饿诱导的糖异生限速酶G6PC和PCK1的表达明显下调(P<0.05)。在肠上皮细胞CaCo-2中过表达SREBP1c,可显著上调糖异生途径关键酶G6PC和PCK1的表达,促进细胞内葡萄糖的产生(P<0.05);反之,敲低SREBP1c的表达,可明显下调G6PC和PCK1,抑制细胞内葡萄糖的产生(P<0.05)。结论饥饿状态下,SREBP1c可调控肠上皮细胞中糖异生限速酶G6PC和PCK1的表达,进而影响葡萄糖的生成,表明SREBP1c可能参与肠道糖异生的调控,机制有待进一步探索。展开更多
Phosphoenolpyruvate carboxykinase 1(PCK1),a step limiting enzyme of gluconeogenesis,is downregulated in hepatocellular carcinoma(HCC).Overexpression of PCK1 has been shown to suppress hepatoma cell growth,but the unde...Phosphoenolpyruvate carboxykinase 1(PCK1),a step limiting enzyme of gluconeogenesis,is downregulated in hepatocellular carcinoma(HCC).Overexpression of PCK1 has been shown to suppress hepatoma cell growth,but the underlying mechanism remains unclear.We used recombinant adenovirus overexpressing PCK1 or GFP in Huh7 cells,and the differentially expressed genes(DEGs)were identified by RNA-Seq.180 were upregulated by PCK1 overexpression,whereas 316 were downregulated.Pathway analysis illustrated that PCK1 was closely correlated with Wnt signaling pathway and TGF-beta signaling pathway.Hence,Wnt signaling pathway and its downstream component,FZD2,FZD6,FZD7 and b-catenin were confirmed by qRT-PCR and Western blot.In vivo we also observed that PCK1 had restrained tumor growth as a result of decreasing expression of b-catenin.Whole-transcriptomic profile analysis discovered that overexpression of PCK1 downregulates several oncogenic signaling pathways in HCC,providing potential therapeutic targets for improving HCC therapy.展开更多
基金This work was supported by The China National Natural Science Foundation,China(No.82073251,82072286,81872270)The Natural Science Foundation Project of Chongqing,China(No.cstc2019jscx-dxwtBX0019,cstc2019jcyj-msxmX0587)+2 种基金The Kuanren Talents Program of The Second Affiliated Hospital of Chongqing Medical University,ChinaThe Future Medical Youth Innovation Team of Chongqing Medical University,China(No.W0036,W0101)The Science and Technology Research Program of Chongqing Municipal Education Commission,China(No.HZ2021006,KJZD-M202000401,KJQN201900429).
文摘The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming.One of the most important cancer hallmarks,including aerobic glycolysis(the Warburg effect),the central carbon pathway,and multiple-branch metabolic pathway remodeling,enables tumor growth,progression,and metastasis.Phosphoenolpyruvate carboxykinase1(PCK1),a key rate-limiting enzyme in gluconeogenesis,catalyzes the conversion of oxaloacetate to phosphoenolpyruvate.PCK1 expression in gluconeogenic tissues is tightly regulated during fasting.In tumor cells,PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracellular environment.Interestingly,PCK1has ananti-oncogenic role in gluconeogenic organs(the liver and kidneys),but a tumor-promoting role in cancers arising from non-gluconeogenic organs.Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways.Aberrant PCK1 expression results in the activation of oncogenic pathways,accompanied by metabolic reprogramming,to maintain tumorigenesis.In this review,we summarize the mechanisms underlying PCK1 expression and regulation,and clarify the crosstalk between aberrant PCK1 expression,metabolic rewiring,and signaling pathway activation.In addition,we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.
文摘目的研究固醇调节元件结合蛋白1c(sterol regulatory element binding protein 1c,SREBP1c)对肠道糖异生的调控作用。方法饥饿处理C57BL/6小鼠、SREBP1c纯合敲除型(SREBP1c-KO)和同窝野生型(SREBP1c-WT)小鼠,通过qPCR、Western blot检测糖异生途径限速酶葡萄糖-6-磷酸酶(glucose-6-phosphatase catalytic,G6PC)和磷酸烯醇式丙酮酸羧激酶(phosphoenolpyruvate carboxykinase 1,PCK1)在肝脏、空肠和回肠组织中的表达水平;在肠上皮细胞CaCo-2中过表达或敲低SREBP1c,检测细胞内G6PC和PCK1表达水平。结果饥饿处理后,C57BL/6小鼠空肠、回肠组织中G6PC、PCK1和SREBP1c表达水平均显著增加(P<0.05)。SREBP1c基因敲除后,小鼠空肠、回肠组织中由饥饿诱导的糖异生限速酶G6PC和PCK1的表达明显下调(P<0.05)。在肠上皮细胞CaCo-2中过表达SREBP1c,可显著上调糖异生途径关键酶G6PC和PCK1的表达,促进细胞内葡萄糖的产生(P<0.05);反之,敲低SREBP1c的表达,可明显下调G6PC和PCK1,抑制细胞内葡萄糖的产生(P<0.05)。结论饥饿状态下,SREBP1c可调控肠上皮细胞中糖异生限速酶G6PC和PCK1的表达,进而影响葡萄糖的生成,表明SREBP1c可能参与肠道糖异生的调控,机制有待进一步探索。
基金We would like to thank Dr.Tong-Chuan He(University of Chicago,USA)for providing the AdEasy system.This study was supported by research grants from China National Natural Science Foundation(grant nos.81602417 to KW,and 81872270 and 81572683 to NT),the Major National S&T program(2017ZX10202203-004 to NT)Natural Science Foundation Project of CQ CSTC(grant no.cstc2018jcyjAX0254 to NT)The Program for Innovation Team of Higher Education in Chongqing(grant no.CXTDX201601015).
文摘Phosphoenolpyruvate carboxykinase 1(PCK1),a step limiting enzyme of gluconeogenesis,is downregulated in hepatocellular carcinoma(HCC).Overexpression of PCK1 has been shown to suppress hepatoma cell growth,but the underlying mechanism remains unclear.We used recombinant adenovirus overexpressing PCK1 or GFP in Huh7 cells,and the differentially expressed genes(DEGs)were identified by RNA-Seq.180 were upregulated by PCK1 overexpression,whereas 316 were downregulated.Pathway analysis illustrated that PCK1 was closely correlated with Wnt signaling pathway and TGF-beta signaling pathway.Hence,Wnt signaling pathway and its downstream component,FZD2,FZD6,FZD7 and b-catenin were confirmed by qRT-PCR and Western blot.In vivo we also observed that PCK1 had restrained tumor growth as a result of decreasing expression of b-catenin.Whole-transcriptomic profile analysis discovered that overexpression of PCK1 downregulates several oncogenic signaling pathways in HCC,providing potential therapeutic targets for improving HCC therapy.
