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Nat Commun. 2014 Mar 17;5:3480. doi: 10.1038/ncomms4480.

Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway.

Author information

1
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
2
1] Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo 160-8582, Japan.
3
1] Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan [2] MS Business Unit, Shimadzu Corporation, Kyoto 604-8511, Japan.

Abstract

Haem oxygenase (HO)-1/carbon monoxide (CO) protects cancer cells from oxidative stress, but the gas-responsive signalling mechanisms remain unknown. Here we show using metabolomics that CO-sensitive methylation of PFKFB3, an enzyme producing fructose 2,6-bisphosphate (F-2,6-BP), serves as a switch to activate phosphofructokinase-1, a rate-limiting glycolytic enzyme. In human leukaemia U937 cells, PFKFB3 is asymmetrically di-methylated at R131 and R134 through modification by protein arginine methyltransferase 1. HO-1 induction or CO results in reduced methylation of PFKFB3 in varied cancer cells to suppress F-2,6-BP, shifting glucose utilization from glycolysis toward the pentose phosphate pathway. Loss of PFKFB3 methylation depends on the inhibitory effects of CO on haem-containing cystathionine β-synthase (CBS). CBS modulates remethylation metabolism, and increases NADPH to supply reduced glutathione, protecting cells from oxidative stress and anti-cancer reagents. Once the methylation of PFKFB3 is reduced, the protein undergoes polyubiquitination and is degraded in the proteasome. These results suggest that the CO/CBS-dependent regulation of PFKFB3 methylation determines directional glucose utilization to ensure resistance against oxidative stress for cancer cell survival.

PMID:
24633012
PMCID:
PMC3959213
DOI:
10.1038/ncomms4480
[Indexed for MEDLINE]
Free PMC Article

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