FOXM1D potentiates PKM2-mediated tumor glycolysis and angiogenesis.
FOXM1D potentiates PKM2-mediated tumor glycolysis and angiogenesis.
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FOXM1D 增强 PKM2 介导的肿瘤糖酵解和血管生成
DOI：
10.1002/1878-0261.12879
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发表时间：
2021-05
影响因子：
6.6
通讯作者：
Hu W
中科院分区：
文献类型：
--
作者：
Zhang W;Zhang X;Huang S;Chen J;Ding P;Wang Q;Li L;Lv X;Li L;Zhang P;Zhou D;Wen W;Wang Y;Lei QY;Wu J;Hu W
FOXM1D与四聚体PKM2结合并组装异构体，从而促进有氧糖酵解。此外，FOXM1D与PKM2和NF - κB相互作用，并通过输入蛋白4诱导其核易位。核PKM2和NF - κB复合物随后增强VEGFA转录。增加的VEGFA通过外泌体在细胞外分泌，FOXM1与VPS11的相互作用增强了这一事件，最终促进肿瘤血管生成。肿瘤的生长，尤其是晚期，需要充足的营养和丰富的脉管系统，PKM2在其中起着聚集作用。据报道，PKM2和FOXM1D在晚期结直肠癌中表达上调，并与转移相关；然而，它们促进肿瘤进展的潜在机制尚不清楚。在此，我们发现FOXM1D通过多种蛋白相互作用增强PKM2介导的糖酵解和血管生成。在FBP存在的情况下，FOXM1D与四聚体PKM2结合并组装一个异二聚体，将PKM2的代谢活性抑制约一半，从而促进有氧糖酵解。此外，FOXM1D与PKM2和NF‐κB相互作用，并在核转运蛋白输入的帮助下诱导其核易位4。一旦进入细胞核，PKM2和NF - κB复合物随后增强VEGFA转录。增加的VEGFA通过外泌体在细胞外分泌，FOXM1与VPS11的相互作用增强了这一事件，最终促进肿瘤血管生成。基于这些发现，我们的研究为PKM2在糖酵解和血管生成调控中的作用提供了另一种见解。
FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, thereby promoting aerobic glycolysis. Further, FOXM1D interacts with PKM2 and NF‐κB and induces their nuclear translocation via importin 4. The nuclear PKM2 and NF‐κB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis. Tumor growth, especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role. It has been reported that PKM2, together with FOXM1D, is upregulated in late‐stage colorectal cancer and associated with metastasis; however, their underlying mechanism for promoting tumor progression remains elusive. Herein, we revealed that FOXM1D potentiates PKM2‐mediated glycolysis and angiogenesis through multiple protein–protein interactions. In the presence of FBP, FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, restraining PKM2 metabolic activity by about a half and thereby promoting aerobic glycolysis. Furthermore, FOXM1D interacts with PKM2 and NF‐κB and induces their nuclear translocation with the assistance of the nuclear transporter importin 4. Once in the nucleus, PKM2 and NF‐κB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis. Based on these findings, our study provides another insight into the role of PKM2 in the regulation of glycolysis and angiogenesis.
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