Stabilization of AMPK/PFKL/RPIA in the Glycolytic Bodies Transduces IL6/STAT3 Signal in Hepatocarcinogenesis

Metabolic reprogramming is a pivotal characteristic of cancer, yet the intricate interplay between glycolysis and the pentose phosphate pathway (PPP) remains elusive. This study unveils the pivotal role of 6-phosphofructokinase liver type (PFKL) in glycolysis and ribose 5-phosphate isomerase A (RPIA...

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Published inbioRxiv
Main Authors He-Yun, Hsiao, Chun-Chia, Cheng, Yu-Ting, Chou, Cheng-Chin, Kuo, Wang, Wen-Ching, Bonifasius Putera Sampurna, Yi-Wen, Wang, Chun-Ling, Hsiao, Wu, Jing-Yiing, Kuan-Hao, Lin, Wan-Yu, Yang, Yu-Hsuan, Lin, Kong-Huai Gwee, Wang, Horng-Dar, Chiou-Hwa Yuh
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 04.03.2024
Subjects
6-Phosphofructokinase
Cancer therapies
Cell migration
Cell proliferation
Cirrhosis
Complementation
Glycolysis
Hepatitis
Hepatocellular carcinoma
Hepatoma
Inflammation
Interleukin 6
Liver cancer
Pentose phosphate pathway
Phosphofructokinase
Proteasomes
Stat3 protein
Tumorigenesis
Ubiquitination
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Summary:Metabolic reprogramming is a pivotal characteristic of cancer, yet the intricate interplay between glycolysis and the pentose phosphate pathway (PPP) remains elusive. This study unveils the pivotal role of 6-phosphofructokinase liver type (PFKL) in glycolysis and ribose 5-phosphate isomerase A (RPIA) in PPP, orchestrating liver tumorigenesis. PFKL, the rate-limiting enzyme in glycolysis, stabilizes RPIA by impeding ubiquitination/proteasome activity. The pro-inflammatory and tumor cytokine interleukin 6 activates pSTAT3 which binds to the promoter region and activates AMPK and PFKL transcription. Furthermore, pAMPK stabilizes PFKL protein by preventing proteasome degradation in hepatoma cells. Inhibiting PFKL, AMPK, and STAT3 genetically or pharmacologically can reduce glycolysis, ATP production, resulting in reduction of hepatoma cell proliferation and migration. Intriguingly, the PFKL, AMPK, RPIA, and PKM2 are co-localized in the Glycolytic body (G-body) which starts forming at chronic hepatitis, dramatically increases during active hepatitis, and the size of G-bodies becomes bigger from cirrhosis to hepatocellular carcinoma. Furthermore, using Bimolecular fluorescence complementation (BiFC) assay, we demonstrated that PFKL and RPIA direct interacts. Targeting AMPK or STAT3 significantly reduced tumor formation and lipid accumulation in zebrafish models, suggesting the STAT3/AMPK/PFKL axis as a potential therapeutic avenue for liver cancer treatment.Competing Interest StatementThe authors have declared no competing interest.
DOI:10.1101/2024.02.29.582877