Mitochondrial free fatty acid β-oxidation supports oxidative phosphorylation and proliferation in cancer cells

Rodrı́guez-Enrı́quez, Sara; Hernández‐Esquivel, Luz; Marín‐Hernández, Álvaro; Hafidi, Mohammed El; Gallardo‐Pérez, Juan Carlos; Hernández‐Reséndiz, Ileana; Rodríguez‐Zavala, José S.; Pacheco-Velázquez, Silvia Cecilia; Moreno‐Sánchez, Rafael

doi:10.1016/j.biocel.2015.06.010

Cited by 62 publications

(50 citation statements)

References 99 publications

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“…FAO inhibitors are promising candidates for consideration in cancer treatment (Carracedo et al, 2013; Heřmanová et al, 2015; Rodríguez-Enríquez et al, 2015). The utility of FAO inhibitors would be greatly aided by biomarkers that identify individuals who might most likely benefit from such a treatment.…”

Section: Discussionmentioning

confidence: 99%

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

et al. 2016

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SUMMARY While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.

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Section: Discussionmentioning

confidence: 99%

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

et al. 2016

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“…In breast cancer cells, perhexiline has been shown to inhibit HER3-signaling [34] and induce autophagy [35]. It is not known whether these effects are caused directly by the compound or are down-stream effects from inhibition of lipid metabolism, as it is well established that perhexiline affects lipid metabolism of cancer cells [36, 37]. Interestingly, a number of studies have reported that perhexiline is able to sensitize, and in some cases, reverse resistance, to clinically relevant drugs, including doxorubicin in breast cancer cells [38] and murine leukemia cell line [39] and cisplatin in neuroblastoma cells [40].…”

Section: Discussionmentioning

confidence: 99%

Lipid degradation promotes prostate cancer cell survival

et al. 2017

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Prostate cancer is the most common male cancer and androgen receptor (AR) is the major driver of the disease. Here we show that Enoyl-CoA delta isomerase 2 (ECI2) is a novel AR-target that promotes prostate cancer cell survival. Increased ECI2 expression predicts mortality in prostate cancer patients (p = 0.0086). ECI2 encodes for an enzyme involved in lipid metabolism, and we use multiple metabolite profiling platforms and RNA-seq to show that inhibition of ECI2 expression leads to decreased glucose utilization, accumulation of fatty acids and down-regulation of cell cycle related genes. In normal cells, decrease in fatty acid degradation is compensated by increased consumption of glucose, and here we demonstrate that prostate cancer cells are not able to respond to decreased fatty acid degradation. Instead, prostate cancer cells activate incomplete autophagy, which is followed by activation of the cell death response. Finally, we identified a clinically approved compound, perhexiline, which inhibits fatty acid degradation, and replicates the major findings for ECI2 knockdown. This work shows that prostate cancer cells require lipid degradation for survival and identifies a small molecule inhibitor with therapeutic potential.

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“…It plays an important role in various aspects of cancer development and progression (Tirado-Velez et al, 2012,Rodriguez-Enriquez et al, 2015Padanad et al, 2016). The b-oxidation enzymes, the trifunctional proteins:…”

Section: Fatty Acid Synthesis and B-oxidationmentioning

confidence: 99%

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

Saavedra‐García

Nichols

Mahmud

et al. 2018

Molecular and Cellular Endocrinology

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Keywords:Fatty acids Cancer Lipid metabolism FOXO3 FOXM1 AKT/PI3K pathway a b s t r a c t Obesity and cachexia represent divergent states of nutritional and metabolic imbalance but both are intimately linked to cancer. There is an extensive overlap in their signalling pathways and molecular components involved such as fatty acids (FAs), which likely play a crucial role in cancer. Forkhead box (FOX) proteins are responsible of a wide range of transcriptional programmes during normal development, and the FOXO3-FOXM1 axis is associated with cancer initiation, progression and drug resistance.Free fatty acids (FFAs), FA synthesis and b-oxidation are associated with cancer development and progression. Meanwhile, insulin and some adipokines, that are up-regulated by FAs, are also involved in cancer development and poor prognosis. In this review, we discuss the role of FA metabolism in cancer and how FA metabolism integrates with the FOXO3-FOXM1 axis. These new insights may provide leads to better cancer diagnostics as well as strategies for tackling cancer development, progression and drug resistance.

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Mitochondrial free fatty acid β-oxidation supports oxidative phosphorylation and proliferation in cancer cells

Cited by 62 publications

References 99 publications

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

Lipid degradation promotes prostate cancer cell survival

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

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