Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation.

Abstract

Metabolism is a critical regulator of cell fate determination. Recently, the significance of metabolic reprogramming in environmental adaptation during tumorigenesis has attracted much attention in cancer research. Recurrent mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes have been identified in several cancers, including intrahepatic cholangiocarcinoma (ICC). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which affects the activity of multiple α-KG-dependent dioxygenases including histone lysine demethylases. Although mutant IDH can be detected even in the early stages of neoplasia, how IDH mutations function as oncogenic drivers remains unclear. In this study, we aimed to address the biological effects of IDH1 mutation using intrahepatic biliary organoids (IBOs). We demonstrated that mutant IDH1 increased the formation of IBOs as well as accelerated glucose metabolism. Gene expression analysis and ChIP results revealed the upregulation of platelet isoform of phosphofructokinase-1 (PFKP), which is a rate-limiting glycolytic enzyme, through the alteration of histone modification. Knockdown of the Pfkp gene alleviated the mutant IDH1-induced increase in IBO formation. Notably, the high expression of PFKP was observed more frequently in patients with IDH-mutant ICC compared to in those with wild-type IDH (p < 0.01, 80.9% vs. 42.5%, respectively). Furthermore, IBOs expressing mutant IDH1 survived the suppression of ATP production caused by growth factor depletion and matrix detachment by retaining high ATP levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Our findings provide a systematic understanding as to how mutant IDH induces tumorigenic preconditioning by metabolic rewiring in intrahepatic cholangiocytes.

• Authors: Hiroaki Fujiwara, Keisuke Tateishi, Kento Misumi, Akimasa Hayashi, Kaori Igarashi, Hiroyuki Kato, Takuma Nakatsuka, Nobumi Suzuki, Keisuke Yamamoto, Yotaro Kudo, Yoku Hayakawa, Hayato Nakagawa, Yasuo Tanaka, Hideaki Ijichi, Hirofumi Kogure, Yosuke Nakai, Hiroyuki Isayama, Kiyoshi Hasegawa, Masashi Fukayama, Tomoyoshi Soga, Kazuhiko Koike
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 18859 (12 11 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31827136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glutarates
• Ketoglutaric Acids
• alpha-hydroxyglutarate
• Isocitrate Dehydrogenase
• IDH1 protein, human
• Phosphofructokinase-1
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Animals
• Biliary Tract (metabolism)
• Citric Acid Cycle
• Gene Expression Regulation
• Glutarates (metabolism)
• Humans
• Isocitrate Dehydrogenase (genetics, metabolism)
• Ketoglutaric Acids (metabolism)
• Mice
• Mutation
• Phosphofructokinase-1 (genetics, metabolism)