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突变型KRAS在胰腺导管腺癌代谢中的作用

陈懿 谢黎 吴健

引用本文:
Citation:

突变型KRAS在胰腺导管腺癌代谢中的作用

DOI: 10.3969/j.issn.1001-5256.2022.12.043
基金项目: 

国家自然科学基金面上项目 81871997;

国家自然科学基金面上项目 82170624

利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:陈懿对本文的思路和撰写有关键贡献;谢黎参与起草或修改文章关键内容;吴健负责文字的修改与定稿。
详细信息
    通信作者:

    吴健, jian.wu@fudan.edu.cn

Role of KRAS mutation in metabolism of pancreatic ductal adenocarcinoma

Research funding: 

National Science Foundation of China 81871997;

National Science Foundation of China 82170624

More Information
  • 摘要: 胰腺癌作为一种致死率高、预后差的恶性肿瘤,肿瘤代谢相关的基因突变被认为是其进展和预后不良的基础。胰腺导管腺癌(PDAC)是最常见的胰腺癌类型,86%的PDAC患者被检测出KRAS突变,KRAS作为多种信号通路和转录因子上游的“分子开关”,对肿瘤细胞代谢过程起着重要的调控作用。突变型KRAS可影响营养物质和能量代谢重编程、巨胞饮作用和自噬,调节肿瘤微环境中的成分相互作用,维持癌细胞的生存和增殖。目前,临床上对PDAC的KRAS靶向治疗大多停留在试验阶段,未来能否真正应用于治疗仍需进一步临床研究。

     

  • 图  1  KRAS信号通路及其对细胞功能的作用

    注:KRAS在与GTP结合时被激活,启动下游多种信号通路,最终促进细胞存活、增殖、转化、侵袭、胞吞/胞吐功能。KRAS的突变破坏RAS的内在GTP酶活性,使GAP失去对GTP的失活作用,促进GTP向GDP转化,导致KRAS及其下游信号通路的持续激活。GEF:鸟苷酸交换因子;RALGEF:鸟嘌呤核苷酸交换因子;RALA:Ras样蛋白A;RALB:Ras样蛋白B;PLC:磷酯酶C;NK-κB:核因子κB;MEKK1/2/3/4:MAPK激酶1/2/3/4;JNK:c-Jun氨基末端激酶。

    Figure  1.  KRAS signaling pathway and its effects on cell function

    图  2  KRAS突变影响胰腺导管腺癌代谢重编程

    注:葡萄糖在胞液中可裂解为丙酮酸,是葡萄糖无氧氧化和有氧氧化的共同起始途径。在正常细胞中,氧供充足,丙酮酸主要进入线粒体,经历三羧酸循环,遵循糖的有氧氧化途径(黑色箭头路线所示)。(1)KRAS突变,致使葡萄糖转运体、糖酵解限速酶、糖代谢分支途径的关键酶(棕色)上调,糖代谢以无氧氧化为主(棕色箭头路线所示),从而促进葡萄糖摄取,增加糖酵解通量。(2)KRAS突变,刺激磷酸甘油酸激酶1向线粒体易位,致使癌细胞中丙酮酸脱氢酶激酶1磷酸化,抑制丙酮酸脱氢酶(蓝色箭头路线所示),从而抑制胰腺癌细胞中线粒体氧化磷酸化,产能减少。GFPT1:谷氨酰胺6-磷酸果糖转移酶;RPE:5-磷酸核丁糖-3-差向异构酶;RPIA:5-磷酸核丁糖异构酶。

    Figure  2.  KRAS mutation affects metabolic reprogramming in pancreatic ductal adenocarcinoma

    表  1  KRAS突变对PDAC代谢的影响

    Table  1.   Effects of KRAS mutations on PDAC metabolism

    影响类型 涉及机制 分子水平改变 最终效应
    肿瘤细胞代谢重编程 糖代谢 上调:葡萄糖转运体、己糖激酶、磷酸果糖激酶1、乳酸脱氢酶、谷氨酰胺6-磷酸果糖转移酶、5-磷酸核丁糖-3-差向异构酶、5-磷酸核丁糖异构酶 葡萄糖摄取↑乳酸产量↑糖酵解通量↑
    磷酸甘油酸激酶1线粒体易位 氧化磷酸化↓能量产生↓
    脂代谢 以细胞外脂质供应占主导 避免损耗,限制细胞死亡
    过度表达酰基辅酶A合成酶长链3 抑制细胞自噬
    氨基酸代谢 诱导:磷酸戊糖途径的代谢重组、天冬氨酸转氨酶的表达 谷氨酰胺代谢↑
    抑制:苹果酸脱氢酶1精氨酸甲基化、谷氨酸脱氢酶的表达、线粒体解耦连蛋白2的表达 维持肿瘤细胞活力
    巨胞饮与自噬作用 巨胞饮 突变型KRAS与肿瘤细胞表面的αvβ3和半乳糖凝集素3形成复合物 癌细胞巨胞饮作用↑
    促进关键效应因子V-ATPase向质膜易位 维持癌细胞的氧化还原平衡
    自噬 激活YAP-TAZ途径及其下游JAK-STAT3信号转导 诱导细胞自噬相关的MHC-I降解
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  • 收稿日期:  2022-05-24
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  • 出版日期:  2022-12-20
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