Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival

作者：Monika Komza, Jesminara Khatun, Jesse D. Gelles, Andrew Trotta, Ioana Abraham‐Enachescu, Juan Henao, Ahmed M. Elsaadi, Andriana G. Kotini, Cara Clementelli, Joann Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Mirela Berisa, Bridget K. Marcellino, Eirini P. Papapetrou, Masha V. Poyurovsky, Jerry E. Chipuk · 发表于：Cell Communication and Signaling · 年份：2025 · DOI：10.1186/s12964-025-02044-y · 被引用次数：7 · 研究领域：Acute Myeloid Leukemia Research、Cancer, Hypoxia, and Metabolism、Histone Deacetylase Inhibitors Research

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial r...