Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors
| Autor: | Xuemei Yu, Ji-In Kim, Anthony Barsotti, Milica Momcilovic, Christophe Lamarque, Jeegar Patel, Masha V. Poyurovsky, Jack Gaffney, Koi Morris, Joshua D. Rabinowitz, Kevin G. Liu, David B. Shackelford, Kellen L. Olszewski, Xiao-Jiang Feng |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Aspartic Acid Clinical Biochemistry Citric Acid Cycle Glucose transporter SDHA Malate-aspartate shuttle Oxidative phosphorylation Metabolism Synthetic lethality Mitochondrion Biology Biochemistry Cell biology Mitochondria Citric acid cycle Glucose Neoplasms Drug Discovery Molecular Medicine Humans Molecular Biology |
| Zdroj: | Cell chemical biology. 29(3) |
| ISSN: | 2451-9448 |
| Popis: | Summary Efforts to target glucose metabolism in cancer have been limited by the poor potency and specificity of existing anti-glycolytic agents and a poor understanding of the glucose dependence of cancer subtypes in vivo. Here, we present an extensively characterized series of potent, orally bioavailable inhibitors of the class I glucose transporters (GLUTs). The representative compound KL-11743 specifically blocks glucose metabolism, triggering an acute collapse in NADH pools and a striking accumulation of aspartate, indicating a dramatic shift toward oxidative phosphorylation in the mitochondria. Disrupting mitochondrial metabolism via chemical inhibition of electron transport, deletion of the malate-aspartate shuttle component GOT1, or endogenous mutations in tricarboxylic acid cycle enzymes, causes synthetic lethality with KL-11743. Patient-derived xenograft models of succinate dehydrogenase A (SDHA)-deficient cancers are specifically sensitive to KL-11743, providing direct evidence that TCA cycle-mutant tumors are vulnerable to GLUT inhibitors in vivo. |
| Databáze: | OpenAIRE |
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