Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming
| Autor: | James D. Griffin, Haymanti Bhanot, Richard Stone, Ellen Weisberg, Donna Neuberg, Klaus Podar, Ravi Salgia, Atsushi Nonami, Martin Sattler, Mamatha M. Reddy |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Daunorubicin cancer metabolism Pentose phosphate pathway 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine acute myeloid leukemia (AML) hemic and lymphatic diseases medicine Kinase activity FLT3 6-phosphogluconate dehydrogenase (6PGD) Quizartinib drug resistance Cell growth business.industry Myeloid leukemia Cancer medicine.disease 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Immunology Cancer research Cytarabine business Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Haymanti Bhanot 1, 2 , Ellen L. Weisberg 1, 2 , Mamatha M. Reddy 1, 2, 7 , Atsushi Nonami 1, 2, 8 , Donna Neuberg 3 , Richard M. Stone 1, 2 , Klaus Podar 4, 5 , Ravi Salgia 6 , James D. Griffin 1, 2 and Martin Sattler 1, 2 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 2 Department of Medicine, Harvard Medical School, Boston, MA, USA 3 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA 4 Karl Landsteiner University of Health Sciences, University Hospital Krems, Krems an der Donau, Austria 5 German Cancer Research Center (DKFZ), Heidelberg, Germany 6 Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA 7 Present address: LV Prasad Eye Institute, Bhubaneswar, India 8 Present address: Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan Correspondence to: Martin Sattler, email: martin_sattler@dfci.harvard.edu Keywords: acute myeloid leukemia (AML), 6-phosphogluconate dehydrogenase (6PGD), cancer metabolism, FLT3, drug resistance Received: July 22, 2016 Accepted: June 03, 2017 Published: June 28, 2017 ABSTRACT Acute myeloid leukemia (AML) cells are highly dependent on glycolytic pathways to generate metabolic energy and support cell growth, hinting at specific, targetable vulnerabilities as potential novel targets for drug development. Elevated levels of NADPH, a central metabolic factor involved in redox reactions, are common in myeloid leukemia cells, but the significance or biochemical basis underlying this increase is unknown. Using a small molecule analog that efficiently inhibits NADPH-producing enzymes, we found that AML cells require NADPH homeostasis for cell growth. We also found that inhibiting NADPH production through knockdown of 6-phosphogluconate dehydrogenase (6PGD) within the pentose phosphate pathway was sufficient to reduce cell growth and lactate production, a measure of metabolic reprogramming. Further, inhibition of 6PGD activity reduced NADH levels and enzymatic activity of the oxidized NADH-dependent sirtuin-1. Targeting 6PGD and NADPH production was sufficient to block growth of AML cell lines resistant to the chemotherapeutics daunorubicin and cytarabine. Importantly, stromal cell-mediated resistance to targeted inhibition of oncogenic FLT3 kinase activity by quizartinib was circumvented by 6PGD knockdown. Overall, these data suggest that the dependency of AML cells on NADPH to permit increased glycolytic flux creates a potential vulnerability of possible therapeutic benefit, since much of the enhanced production of NADPH is dependent on the activity of a single enzyme, 6PGD. |
| Databáze: | OpenAIRE |
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