KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2  

作　　者：Chaofan Peng Peng Yang Dongsheng Zhang Chi Jin Wen Peng Tuo Wang Qingyang Sun Zhihao Chen Yifei Feng Yueming Sun 

机构地区：[1]Department of General Surgery,the First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China [2]Colorectal Institute of Nanjing Medical University,Nanjing 210029,China [3]The First School of Clinical Medicine,Nanjing Medical University,Nanjing 210029,China [4]Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine,Nanjing 210029,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期2959-2976,共18页药学学报（英文版）

基　　金：funded by the National Natural Science Foundation(Grant Number 82273406);Basic Research Program of Jiangsu Province(Grant No.BK20201491,China);Nature Key Research and Development Program of Jiangsu Province(BE2021742,China);Jiangsu Province Capability Improvement Project through Science,Technology and Education(Jiangsu Provincial Medical Key Discipline,ZDXK202222,China);the National Natural Science Foundation(Grant Number 82203656,China).

摘　　要：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.

关 键 词：CRC CRLM FRUCTOSE KHK-A PKM2 

分 类 号：R735[医药卫生—肿瘤]