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Targeting Host Glycolysis as a Strategy for Antimalarial Development.

ABSTRACT: Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase - a critical enzyme in glycolysis - and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of Plasmodium falciparum malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity in malaria parasite growth.

SUBMITTER: Jezewski AJ

PROVIDER: S-EPMC8482815 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Targeting Host Glycolysis as a Strategy for Antimalarial Development.

Jezewski Andrew J AJ Lin Yu-Hsi YH Reisz Julie A JA Culp-Hill Rachel R Barekatain Yasaman Y Yan Victoria C VC D'Alessandro Angelo A Muller Florian L FL Odom John Audrey R AR

Frontiers in cellular and infection microbiology 20210916

Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed speci ...[more]

PMID: 34604112

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Project description:BackgroundInfantile hemangioma (IH) is the most common tumor among infants, but the exact pathogenesis of IH is largely unknown. Our previous study revealed that glucose metabolism may play an important role in the pathogenesis of IH and that the inhibition of the glycolytic key enzyme phosphofructokinase-1 suppresses angiogenesis in IH. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a metabolic enzyme that converts fructose-6-bisphosphate to fructose-2,6-bisphosphate (F-2,6-BP), which is the most potent allosteric activator of the rate-limiting enzyme phosphofructokinase-1. This study was performed to explore the role of PFKFB3 in IH.MethodsMicroarray analysis was performed to screen the differentially expressed genes (DEGs) between proliferating and involuting IH tissues. PFKFB3 expression was examined by western blot and immunohistochemistry analyses. Cell migration, apoptosis and tube formation were analyzed. Metabolic analyses were performed to investigate the effect of PFKFB3 inhibition by PFK15. Mouse models were established to examine the effect of PFKFB3 inhibition in vivo.ResultsPFKFB3 was identified as one of the most significant DEGs and was more highly expressed in proliferating IH tissues and hemangioma-derived endothelial cells (HemECs) than in involuting IH tissues and human umbilical vein endothelial cells, respectively. PFKFB3 inhibition by PFK15 suppressed HemEC glucose metabolism mainly by affecting glycolytic metabolite metabolism and decreasing the glycolytic flux. Moreover, PFK15 inhibited HemEC angiogenesis and migration and induced apoptosis via activation of the apoptosis pathway. Treatment with the combination of PFK15 with propranolol had a synergistic inhibitory effect on HemECs. Moreover, PFKFB3 knockdown markedly suppressed HemEC angiogenesis. Mechanistically, inhibition of PFKFB3 suppressed the PI3K-Akt signaling pathway and induced apoptotic cell death. More importantly, the suppression of PFKFB3 by PFK15 or shPFKFB3 led to markedly reduced tumor growth in vivo.ConclusionsOur findings suggest that PFKFB3 inhibition can suppress IH angiogenesis and induce apoptosis. Thus, targeting PFKFB3 may be a novel therapeutic strategy for IH.

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Targeting Host Glycolysis as a Strategy for Antimalarial Development.

Publications

Targeting Host Glycolysis as a Strategy for Antimalarial Development.

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