PDF(Pubmed)
Abstract：
Excessive fructose diet is closely associated with colorectal cancer (CRC) progression. Nevertheless, fructose\'s specific function and precise mechanism in colorectal cancer liver metastasis (CRLM) is rarely known. Here, this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM, and the expression of KHK-A, not KHK-C, in liver metastasis was higher than in paired primary tumors. Furthermore, KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37. PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2. EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells\' migration ability and anoikis resistance during CRLM progression. TEPP-46 treatment, targeting the phosphorylation of PKM2, inhibited the pro-metastatic effect of KHK-A. Besides, c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A, forming a positive feedback loop.
摘要：
过量果糖饮食与结直肠癌(CRC)进展密切相关。然而，果糖在结直肠癌肝转移(CRLM)中的具体功能和确切机制鲜为人知。这里,这项研究报道，原发性结直肠癌吸收的果糖可以加速CRLM，和KHK-A的表达式，不是KHK-C,在肝转移中高于配对的原发性肿瘤。此外，KHK-A通过在Ser37磷酸化PKM2在体外和体内促进果糖依赖性CRLM。KHK-A磷酸化的PKM2抑制了其四聚体的形成和丙酮酸激酶的活性，但促进了PKM2的核积累。核PKM2激活的EMT和有氧糖酵解可增强CRLM过程中CRC细胞的迁移能力和抗肛门凋亡能力。TEPP-46处理，靶向PKM2的磷酸化，抑制KHK-A的促转移作用。此外,核PKM2激活的c-myc促进KHK-A的选择性剪接，形成正反馈回路。
