High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

Liu, Longlong; Patnana, Pradeep Kumar; Xie, Xiaoqing; Frank, Daria; Nimmagadda, Subbaiah Chary; Rosemann, Annegret; Liebmann, Marie; Klotz, Luisa; Opalka, Bertram; Khandanpour, Cyrus

doi:10.3390/cancers14030486

Cited by 14 publications

(9 citation statements)

References 37 publications

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“…5a ). We observed a substantial decrease in colony numbers of rotenone-treated Gfi1b -WT and Gfi1b -KO MLL/AF9 cells, which supported our previous report about the high dependence on OXPHOS of MLL/AF9 leukemia [ 27 ]. Untreated Gfi1b -KO leukemic cells generated more colonies than Gfi1b -WT cells, but Gfi1b -KO cells treated with etomoxir generated a similar number of colonies as Gfi1b -WT cells, indicating that FAO inhibition significantly impeded the rapid progression of Gfi1b-deficient leukemic cells (Fig.…”

Section: Resultssupporting

confidence: 91%

GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia

et al. 2022

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Recent studies highlighted the role of transcription factors in metabolic regulation during hematopoiesis and leukemia development. GFI1B is a transcriptional repressor that plays a critical role in hematopoiesis, and its expression is negatively related to the prognosis of acute myeloid leukemia (AML) patients. We earlier reported a change in the metabolic state of hematopoietic stem cells upon Gfi1b deletion. Here we explored the role of Gfi1b in metabolism reprogramming during hematopoiesis and leukemogenesis. We demonstrated that Gfi1b deletion remarkably activated mitochondrial respiration and altered energy metabolism dependence toward oxidative phosphorylation (OXPHOS). Mitochondrial substrate dependency was shifted from glucose to fatty acids upon Gfi1b deletion via upregulating fatty acid oxidation (FAO). On a molecular level, Gfi1b epigenetically regulated multiple FAO-related genes. Moreover, we observed that metabolic phenotypes evolved as cells progressed from preleukemia to leukemia, and the correlation between Gfi1b expression level and metabolic phenotype was affected by genetic variations in AML cells. FAO or OXPHOS inhibition significantly impeded leukemia progression of Gfi1b-KO MLL/AF9 cells. Finally, we showed that Gfi1b-deficient AML cells were more sensitive to metformin as well as drugs implicated in OXPHOS and FAO inhibition, opening new potential therapeutic strategies.

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Section: Resultssupporting

confidence: 91%

GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia

et al. 2022

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“…Similar to a growing list of human solid organ malignancies, AML is particularly reliant on oxidative metabolism [1][2][3][4][5][6][7] . Pioneering studies over the past several years have repeatedly demonstrated potent antileukemic effects upon targeting AML's mitochondrial reliance [8][9][10][11][12][13][14][15] . Although mitochondrial targeted therapies are entering clinical trials, the majority of hopeful 'mito-therapeutics' suffer from a limited therapeutic index based on their inability to discriminate cancerous from non-cancerous mitochondria 11,[16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

Hagen,

Montgomery,

Aruleba

et al. 2024

Preprint

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Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, primarily stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of our hypothesis, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well the endogenous F1-ATPase inhibitor ATP5IF1. In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.

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“…Even if a slight effect may have been observed in low-grade tumor patients, metformin has no effect on high-grade tumors [ 7 ]. Despite the lack of conclusive results in patients, metformin has demonstrated potent anti-cancer properties in vitro and in preclinical in vivo experimental models [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. These conflicting results raise questions about the response of cancer cells to metformin.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have shown that metformin targets mitochondria, thereby perturbing cellular energetics, via a mechanism relying on mitochondrial electron transport chain (ETC) complex-I inhibition [ 10 , 11 , 12 , 14 ]. ETC complex-I performs the oxidation of the reduced form of nicotinamide adenine dinucleotide (NADH) to regenerate the NAD + needed as a cofactor for numerous catabolic reactions, including glycolysis, β-oxidation, and the Krebs cycle.…”

Section: Introductionmentioning

confidence: 99%

The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells

Parisotto

Vuong-Robillard

Kalegari

et al. 2022

Cancers

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Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use has been associated with reduced pancreatic cancer incidence and better survival in diabetics. Metformin has been shown to inhibit PDAC cells growth and survival, both in vitro and in vivo. However, clinical trials using metformin have failed to reduce pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirmed that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio, and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio caused PDAC cells to be resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression, increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased the cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cell line xenografts, but not in mice with PANC-1 cell line xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress, providing new insights about the mechanisms leading to cancer cell death.

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High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

Cited by 14 publications

References 37 publications

GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia

GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells

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