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

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

Acta Pharmaceutica Sinica B (Jul 2024)

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

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

Affiliations

Chaofan Peng: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
Peng Yang: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
Dongsheng Zhang: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
Chi Jin: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
Wen Peng: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
Tuo Wang: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
Qingyang Sun: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
Zhihao Chen: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
Yifei Feng: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing 210029, China; Corresponding authors.
Yueming Sun: Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Colorectal Institute of Nanjing Medical University, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing 210029, China; Corresponding authors.

Journal volume & issue: Vol. 14, no. 7
pp. 2959 – 2976

Abstract

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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.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/acta-pharmaceutica-sinica-b

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