Resistance to anoikis in transcoelomic shedding: the role of glycolytic enzymes
Resistance to anoikis in transcoelomic shedding: the role of glycolytic enzymes
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DOI：
10.1515/pp-2019-0003
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发表时间：
2019-03
影响因子：
1.8
通讯作者：
R. Wilson;W. Solass;R. Archid;F. Weinreich;A. Königsrainer;M. Reymond
中科院分区：
文献类型：
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作者：
R. Wilson;W. Solass;R. Archid;F. Weinreich;A. Königsrainer;M. Reymond
细胞脱离细胞外基质进入腹腔，引发一系列代谢改变，通常导致细胞凋亡死亡，即所谓的细胞凋亡。糖酵解酶能够从氧化磷酸化转换到有氧糖酵解，并允许抵抗脱落肿瘤细胞的损伤。这些酶还兼有作为蛋白激酶和转录因子的活性。磷酸甘油酸激酶（PGK）和丙酮酸激酶是在己糖激酶途径中唯一产生ATP的糖酵解酶。缺氧、EGFR激活、K-Ras G12V和B-Raf V600E的表达诱导磷酸甘油酸激酶1 （PGK1）的线粒体易位。线粒体PGK1作为磷酸化丙酮酸脱氢酶激酶1 （PDHK1）的蛋白激酶，减少线粒体丙酮酸的利用，抑制活性氧的产生，增加乳酸的产生，促进肿瘤的发生。一旦转运到细胞核中，PGK1也作为转录因子发挥作用。癌症相关成纤维细胞（CAFs）提供的代谢支持也促进了对癌症的抵抗。我们的一系列体外和动物模型实验表明，PGK1敲除或抑制可有效控制胃源性腹膜转移（PM）的发展和生长，从而确立了PGK1在这一发展中的因果作用。PGK1还增加了CXCR4和CXCL12的表达，这与转移表型有关，并在恶性细胞的转移归巢中发挥作用。因此，PGK1及其调节因子和靶基因可能被用作预防PM发展和增强常规全身化疗的细胞毒性作用的治疗靶点。
Abstract Detachment of cells from the extracellular matrix into the peritoneal cavity initiates a cascade of metabolic alterations, leading usually to cell death by apoptosis, so-called anoikis. Glycolytic enzymes enable the switch from oxidative phosphorylation to aerobic glycolysis and allow resistance to anoikis of shed tumour cells. These enzymes also have moonlighting activities as protein kinases and transcription factors. Phosphoglycerate kinase (PGK) and pyruvate kinase are the only glycolytic enzymes generating ATP in the hexokinase pathway. Hypoxia, EGFR activation, expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1). Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1), reducing mitochondrial pyruvate utilization, suppressing reactive oxygen species production, increasing lactate production and promoting tumourigenesis. PGK1 also plays a role as a transcription factor once transported into the nucleus. Resistance to anoikis is also facilitated by metabolic support provided by cancer-associated fibroblasts (CAFs). Our series of experiments in-vitro and in the animal model showed that PGK1 knock-out or inhibition is effective in controlling development and growth of peritoneal metastasis (PM) of gastric origin, establishing a causal role of PGK1 in this development. PGK1 also increases CXCR4 and CXCL12 expression, which is associated with a metastatic phenotype and plays a role in the metastatic homing of malignant cells. Thus, PGK1, its modulators and target genes may be exploited as therapeutic targets for preventing development of PM and for enhancing cytotoxic effects of conventional systemic chemotherapy.