Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival
Abstract 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...
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BMC
2025-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02044-y |
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| author | Monika Komza Jesminara Khatun Jesse D. Gelles Andrew P. Trotta Ioana Abraham-Enachescu Juan Henao Ahmed 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 Edward Chipuk |
| author_facet | Monika Komza Jesminara Khatun Jesse D. Gelles Andrew P. Trotta Ioana Abraham-Enachescu Juan Henao Ahmed 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 Edward Chipuk |
| author_sort | Monika Komza |
| collection | DOAJ |
| description | Abstract 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 respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success. |
| format | Article |
| id | doaj-art-1ee0edd56afb478b807dd13d66caf1ab |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-1ee0edd56afb478b807dd13d66caf1ab2025-01-26T12:44:50ZengBMCCell Communication and Signaling1478-811X2025-01-0123112310.1186/s12964-025-02044-yMetabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survivalMonika Komza0Jesminara Khatun1Jesse D. Gelles2Andrew P. Trotta3Ioana Abraham-Enachescu4Juan Henao5Ahmed Elsaadi6Andriana G. Kotini7Cara Clementelli8JoAnn Arandela9Sebastian El Ghaity-Beckley10Agneesh Barua11Yiyang Chen12Mirela Berisa13Bridget K. Marcellino14Eirini P. Papapetrou15Masha V. Poyurovsky16Jerry Edward Chipuk17Department of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiThe Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiThe Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiThe Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiDepartment of Ecology and Evolution, University of LausanneDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiMetabolomics Core, Icahn School of Medicine at Mount SinaiThe Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiKadmon PharmaceuticalsDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiAbstract 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 respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.https://doi.org/10.1186/s12964-025-02044-yAdaptationsBioenergeticsCancerChemotherapyGlucoseLeukemia |
| spellingShingle | Monika Komza Jesminara Khatun Jesse D. Gelles Andrew P. Trotta Ioana Abraham-Enachescu Juan Henao Ahmed 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 Edward Chipuk Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival Cell Communication and Signaling Adaptations Bioenergetics Cancer Chemotherapy Glucose Leukemia |
| title | Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival |
| title_full | Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival |
| title_fullStr | Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival |
| title_full_unstemmed | Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival |
| title_short | Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival |
| title_sort | metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival |
| topic | Adaptations Bioenergetics Cancer Chemotherapy Glucose Leukemia |
| url | https://doi.org/10.1186/s12964-025-02044-y |
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