Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids

LeBoeuf, Sarah E.; Wu, Warren; Karakousi, Triantafyllia; Karadal, Burcu; Jackson, Susan; Davidson, Shawn M.; Wong, Kwok-Kin; Koralov, Sergei B.; Sayin, Volkan I.; Papagiannakopoulos, Thales

doi:10.1016/j.cmet.2019.11.012

Cited by 121 publications

(110 citation statements)

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“…Convenient treatment of LSCC remains to be platinum-based chemotherapy, added with immune checkpoint inhibitors that emerged recently and has brought certain benefits for the treatment of LSCC [37]. Additionally, cancer cells acquire novel nutrient dependencies to support oncogenic growth by changing metabolic pathways, Sarah E first points that dietary restriction or enzymatic depletion of asparagine can lead to suppression of Keap1 mutant tumor growth [38]. However, the overall effects of therapy for LSCC remain grim, revealing the immediate need for an effective treatment.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation

Gong

Yan

et al. 2020

Cell Commun Signal

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Background and purpose: Targeted therapy and immunotherapy have led to dramatic change in the treatment of lung cancer, however, the overall 5-year survival rate of lung cancer patients is still suboptimal. It is important to exploit new potential of molecularly targeted therapies. High-frequency somatic mutations in KEAP1/NRF2 (27.9%) have been identified in lung squamous cell carcinoma. In this research, we explored the role of KEAP1 somatic mutations in the development of LSCC and whether a nuclear factor erythroid 2-related factor 2(NRF2) inhibitor be potential to target lung cancer carrying KEAP1/NRF2 mutations. Methods: Lung cancer cell lines A549 and H460 with loss-of-function mutations in KEAP1 stably transfected with wild-type (WT) KEAP1 or somatic mutations in KEAP1 were used to investigate the functions of somatic mutations in KEAP1. Flow cytometry, plate clone formation experiments, and scratch tests were used to examine reactive oxygen species, proliferation, and migration of these cell lines. Results: The expression of NRF2 and its target genes increased, and tumor cell proliferation, migration, and tumor growth were accelerated in A549 and H460 cells stably transfected with KEAP1 mutants compared to control cells with a loss-of-function KEAP1 mutation and stably transfected with WT KEAP1 in both in vitro and in vivo studies. The proliferation of A549 cell line trasfected with the R320Q KEAP1 mutant was inhibited more apparent than that of the A549 cell line trasfected with WT KEAP1 after treatment with NRF2 inhibitor ML385. Conclusion: Somatic mutations of KEAP1 identified from patients with LSCC likely promote tumorigenesis mediated by activation of the KEAP1/NRF2 antioxidant stress response pathway. NRF2 inhibition with ML385 could inhibit the proliferation of tumor cells with KEAP1 mutation.

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Section: Discussionmentioning

confidence: 99%

Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation

Gong

Yan

et al. 2020

Cell Commun Signal

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“…Cancers exposed to high oxidative stress use amino acids to produce antioxidant molecules. Lung adenocarcinomas with nuclear factor erythroid 2-related factor (Nrf)2/ Kelch-like ECHassociated protein (Keap)1 mutations are highly dependent on exogenous non-essential amino acids, and diets lacking asparagine or both serine and glycine reduce Keap1 mutant tumor growth in mice (LeBoeuf et al, 2020). This implicates dietary interventions as potential anti-cancer strategies.…”

Section: Modulation Of Cysteine In Cancer Immunotherapymentioning

confidence: 99%

Amino Assets: How Amino Acids Support Immunity

2020

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Amino acids are fundamental building blocks supporting life. Their role in protein synthesis is well defined, but they contribute to a host of other intracellular metabolic pathways, including ATP generation, nucleotide synthesis, and redox balance, to support cellular and organismal function. Immune cells critically depend on such pathways to acquire energy and biomass and to reprogram their metabolism upon activation to support growth, proliferation, and effector functions. Amino acid metabolism plays a key role in this metabolic rewiring, and it supports various immune cell functions beyond increased protein synthesis. Here, we review the mechanisms by which amino acid metabolism promotes immune cell function, and how these processes could be targeted to improve immunity in pathological conditions.

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“…HSF1 inhibition was sufficient to significantly increase the levels of oxidized glutathione in MECs on stiff PA-gels ( Fig.4F). Metabolomics allowed us to observe that many metabolite changes that reflect OxSR (34), and pentose phosphate pathway activity, which generates reduced nicotinamide adenine dinucleotide phosphate (NADPH) required to regenerate reduced glutathione and mitigate oxidative by inhibiting HSF1 transcriptional activity ( Fig. S4E).…”

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confidence: 99%

Adhesion-mediated mechanosignaling forces mitohormesis

Tharp

Higuchi‐Sanabria

Timblin³

et al. 2020

Preprint

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Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed cell death. The biochemical milieu regulates mitochondrial function and contributes to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of ageing. Extracellular matrix stiffness and cytoskeletal tension are also altered in cancer and in aged tissues. We 5 determined that cytoskeletal tension elicits a mitochondrial stress response that modifies mitochondrial function via SLC9A1-dependent ion exchange and HSF1-dependent transcription. Our data indicate that this cytoskeletal tension-induced mitochondrial stress response, termed mitohormesis, adaptively tunes mitochondrial metabolism and facilitates oxidative stress resilience. These findings demonstrate that cytoskeletal 10 tension regulates mitochondrial function and suggests that mechanical forces influence tissue behavior by modulating mitochondrial metabolism.One Sentence Summary: Adhesion-mediated mechanotransduction programs mitochondrial metabolism through an adaptive stress response.Main Text: Nutrient availability, oxygen content, and pH regulate cellular metabolism. 15Extracellular matrix (ECM) stiffness can change cellular metabolism by regulating the levels and/or activity of cytoplasmic enzymes responsive to cytoskeletal polymerization (1, 2). Many aspects of cellular metabolism depend upon the mitochondria, a key metabolic organelle that is structurally altered by physical forces and the cytoskeleton (3-5). Since mitochondrial structure influences mitochondrial function, we sought to 20 determine if ECM stiffness and cytoskeletal tension influence cellular metabolism by regulating mitochondrial structure and function. Cytoskeletal tension alters mitochondrial structure and functionTo explore associations between ECM stiffness and mitochondrial structure, we examined the mitochondrial morphology of nonmalignant human mammary epithelial 25 cells (MECs; MCF10A) cultured for 24 hours on polyacrylamide hydrogel gels (PA-gel) ranging in elasticity (stiffness) between normal breast stroma (400 Pa) and breast tumors (6k -60k Pa) (6, 7) (tissue culture polystyrene ~3G Pa). MECs cultured on this range of PA-gel elasticities displayed a variety of mitochondrial morphologies, ranging from thin interconnected filaments (400 Pa), to thickened filaments (6k Pa), and then ~300 nM 30 diameter fragments with toroidal shapes (60k Pa) ( Fig.1A and S1A-B). Cells respond to ECM stiffness by ligating ECM adhesion receptors that induce Rho-GTPase-dependent cytoskeletal remodeling and increase actomyosin tension through type-II myosins (8). Pharmacological inhibition of Rho-associated protein kinase (ROCK) with Y27632 or type-II myosins with blebbistatin, reduced the prevalence of the thick toroidal 35 mitochondrial fragments in MECs plated on the stiffest ECM PA-gels (Fig.1A). These data indicate that mitochondrial structure is sensitive to cytoskeletal tension generated in response to stiffness of the ext...

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Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids

Cited by 121 publications

References 61 publications

Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation

Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation

Amino Assets: How Amino Acids Support Immunity

Adhesion-mediated mechanosignaling forces mitohormesis

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