Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation
Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation
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DOI：
10.1038/s41598-019-55211-w
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发表时间：
2019-12-11
影响因子：
4.6
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
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作者：
Fujiwara, Hiroaki;Tateishi, Keisuke;Koike, Kazuhiko
新陈代谢是决定细胞命运的关键因素。近年来，代谢重编程在肿瘤发生过程中环境适应中的意义引起了肿瘤研究的广泛关注。异柠檬酸脱氢酶(IDH)1或2基因的反复突变已在几种癌症中被发现，包括肝内胆管细胞癌(ICC)。突变的IDH将α-酮戊二酸(α-KG)转化为2-羟基戊二酸(2-HG)，从而影响包括组蛋白赖氨酸去甲基酶在内的多种α-KG依赖的双加氧酶的活性。虽然突变的IDH即使在肿瘤的早期阶段也能被检测到，但IDH突变如何作为致癌驱动因素仍不清楚。在这项研究中，我们旨在利用肝内胆汁器官(IBOS)来研究IDH1突变的生物学效应。我们证明了突变的IDH1增加了IBOS的形成，并加速了葡萄糖代谢。基因表达分析和芯片结果显示，通过组蛋白修饰，限速糖酵解酶-1磷酸果糖激酶-1(PFKP)的血小板亚型表达上调。Pfkp基因的敲除减轻了突变的IDH1诱导的IBO形成的增加。值得注意的是，与野生型IDH患者相比，突变型ICC患者的PFKP高表达频率更高(P<；0.01，80.9%vs.42.5%)。此外，表达突变型IDH1的IBOS通过激活5‘-单磷酸腺苷活化蛋白激酶(AMPK)来维持高水平的ATP水平，从而在生长因子耗尽和基质脱落所致的ATP产生抑制中幸存下来。我们的发现提供了一个系统的理解，即突变的IDH是如何通过肝内胆管细胞的代谢重排来诱导致瘤预适应的。
Metabolism is a critical regulator of cell fate determination. Recently, the significance of metabolic reprogramming in environmental adaptation during tumorigenesis has attracted much attention in cancer research. Recurrent mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes have been identified in several cancers, including intrahepatic cholangiocarcinoma (ICC). Mutant IDHs convert alpha-ketoglutarate (alpha-KG) to 2-hydroxyglutarate (2-HG), which affects the activity of multiple alpha-KG-dependent dioxygenases including histone lysine demethylases. Although mutant IDH can be detected even in the early stages of neoplasia, how IDH mutations function as oncogenic drivers remains unclear. In this study, we aimed to address the biological effects of IDH1 mutation using intrahepatic biliary organoids (IBOs). We demonstrated that mutant IDH1 increased the formation of IBOs as well as accelerated glucose metabolism. Gene expression analysis and ChIP results revealed the upregulation of platelet isoform of phosphofructokinase-1 (PFKP), which is a rate-limiting glycolytic enzyme, through the alteration of histone modification. Knockdown of the Pfkp gene alleviated the mutant IDH1-induced increase in IBO formation. Notably, the high expression of PFKP was observed more frequently in patients with IDH-mutant ICC compared to in those with wild-type IDH (p < 0.01, 80.9% vs. 42.5%, respectively). Furthermore, IBOs expressing mutant IDH1 survived the suppression of ATP production caused by growth factor depletion and matrix detachment by retaining high ATP levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Our findings provide a systematic understanding as to how mutant IDH induces tumorigenic preconditioning by metabolic rewiring in intrahepatic cholangiocytes.