The redox requirements of proliferating mammalian cells

Hosios, Aaron M.; Heiden, Matthew G. Vander

doi:10.1074/jbc.tm117.000239

Cited by 112 publications

(96 citation statements)

References 90 publications

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“…After exposure to 10 µM of MEK inhibitor, H295R cells presented a significantly higher lactate/alanine ratio and a higher mitochondrial membrane potential after 12 and 24 hours of treatment. The increased lactate/alanine ratio is associated with cellular redox state reflecting the intracellular NADH/NAD+equilibrium . The redox system is essential in maintaining cellular homeostasis and when a redox imbalance occurs, due to higher production of reactive oxygen species (ROS) or a decrease in endogenous protective antioxidants, cells become vulnerable to apoptosis and necrosis.…”

Section: Discussionmentioning

confidence: 99%

MAPK/ERK pathway inhibition is a promising treatment target for adrenocortical tumors

Pereira

Monteiro

Costa

et al. 2018

J of Cellular Biochemistry

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Unraveling molecular mechanisms that regulate tumor development and proliferation is of the utmost importance in the quest to decrease the high mortality rate of adrenocortical carcinomas (ACC). Our aim was to evaluate the role of two of the mitogen-activated protein kinase (MAPK) signaling pathways (extracellular signal-regulated protein kinases [ERKs 1/2] and p38) in the adrenocortical tumorigenesis, as well as the therapeutic potential of MAPK/ERK inhibition. ERKs 1/2 and p38 activation were evaluated in incidentalomas (INC; n = 10), benign Cushing's syndrome (BCS; n = 12), malignant Cushing's syndrome (MCS; n = 6) and normal adrenal glands (NAG; 8). ACC cell line (H295R) was used to evaluate the ability of PD184352 (0.1, 1, and 10 µM), a specific MEK-MAPK-ERK pathway inhibitor, to modulate cell proliferation, viability, metabolism, and steroidogenesis. ERKs 1/2 activation was significantly higher in MCS (2.83 ± 0.17) compared with NAG (1.00 ± 0.19 "arbitrary units"), INC (1.20 ± 0.13) and BCS (2.09 ± 0.09). Phospho-p38 expression was absent in all the MCS analyzed. MAPK/ERK kinase (MEK) inhibition with PD184352 significantly decreased proliferation as well as steroidogenesis and also increased the redox state of the H295R cells. This data suggests that MEK-MAPK-ERK signaling has a role in adrenocortical tumorigenesis that could be potentially used as a diagnostic marker for malignancy and targeted treatment in ACC.

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Section: Discussionmentioning

confidence: 99%

MAPK/ERK pathway inhibition is a promising treatment target for adrenocortical tumors

Pereira

Monteiro

Costa

et al. 2018

J of Cellular Biochemistry

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“…6 C). Given that fatty acid synthesis is highly NADPH-consuming (Fan et al, 2014; Hosios and Vander Heiden, 2018) and NADPH availability was reduced upon NNT loss, we hypothesized that these increases in fatty acid levels were resultant from increased uptake of exogenous fatty acids. Indeed, we found that NNT-deficient cells exhibited an increased capacity to take up a fluorescent palmitate analogue (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function

Ward

Kang

Falzone

et al. 2020

Journal of Experimental Medicine

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Human lung tumors exhibit robust and complex mitochondrial metabolism, likely precipitated by the highly oxygenated nature of pulmonary tissue. As ROS generation is a byproduct of this metabolism, reducing power in the form of nicotinamide adenine dinucleotide phosphate (NADPH) is required to mitigate oxidative stress in response to this heightened mitochondrial activity. Nicotinamide nucleotide transhydrogenase (NNT) is known to sustain mitochondrial antioxidant capacity through the generation of NADPH; however, its function in non-small cell lung cancer (NSCLC) has not been established. We found that NNT expression significantly enhances tumor formation and aggressiveness in mouse models of lung tumor initiation and progression. We further show that NNT loss elicits mitochondrial dysfunction independent of substantial increases in oxidative stress, but rather marked by the diminished activities of proteins dependent on resident iron-sulfur clusters. These defects were associated with both NADPH availability and ROS accumulation, suggesting that NNT serves a specific role in mitigating the oxidation of these critical protein cofactors.

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“…A potential role for malic enzyme in pyruvate carboxylation suggests use of this enzyme to produce malate could be another pathway for TCA cycle anaplerosis. Of note, this reaction would require NADPH, and may be more favored in cancer cells that exhibit a reduced redox state (Hosios and Vander Heiden, 2018). We also considered phosphoenolpyruvate carboxykinase (PEPCK) or malic enzymes 2 and 3 as possible contributors to pyruvate carboxylation activity, although these reactions are less energetically favorable in the reverse direction in comparison to malic enzyme 1; malic enzyme 1 is cytosolic, which is thought to be a more reducing environment than the mitochondria where malic enzymes 2 and 3 are localized (Hu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma

Lau

Danai

et al. 2020

Preprint

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Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between various cell types within a mixed population can be limited by the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in pancreatic cancer organoid-fibroblast co-cultures and in pancreatic tumors. In these contexts, we find pancreatic cancer cells exhibit increased pyruvate carboxylation relative to fibroblasts, and that this flux depends on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells is necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tumor tissue. Keywordspancreatic cancer, PDAC, organoid culture, pyruvate carboxylase, malic enzyme 1, metabolic heterogeneity

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The redox requirements of proliferating mammalian cells

Cited by 112 publications

References 90 publications

MAPK/ERK pathway inhibition is a promising treatment target for adrenocortical tumors

MAPK/ERK pathway inhibition is a promising treatment target for adrenocortical tumors

Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function

Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma

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