Genomic instability and metabolism in cancer

Li, Haojian; Zimmerman, Susan E.; Weyemi, Urbain

doi:10.1016/bs.ircmb.2021.05.004

Cited by 35 publications

(18 citation statements)

References 101 publications

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“…Specifically, whereas TBK1 catalyses mainly the activating phosphorylation of interferon regulatory factor 3 (IRF3), NIK and IKK promote non-canonical NF-κB signalling and canonical NF-κB signalling , respectively 25 , 211 . IRF3 activation by STING1 generally results in potent type I interferon responses that are associated with antiviral and anticancer effects 46 , whereas the net outcome of NF-κB signalling elicited by cGAS differs depending on setting, ranging from immunostimulation coupled to efficient cancer immunosurveillance (as in the case of canonical NF-κB responses elicited in the course of immunogenic cell death) 212 to indolent inflammation favouring metastatic cancer dissemination (as in the case of non-canonical NF-κB responses driven by genomic instability) 213 , 214 .…”

Section: Mtdamp Signalling Pathwaysmentioning

confidence: 99%

Mitochondrial control of inflammation

et al. 2022

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Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.

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Section: Mtdamp Signalling Pathwaysmentioning

confidence: 99%

Mitochondrial control of inflammation

et al. 2022

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“…MDA-MB-231 cells were pre-treated with the ATM inhibitor AZD1390 as indicated (10, 30, 50, 100 nM) for 1 h followed by the addition of H 2 O 2 (500 μM) for 30 min. Phospho-p53-Ser 15 (p-p53) and phospho-ATM-Ser 1981 (p-ATM) induced by H 2 O 2 were probed by western blot and analyzed for ATM kinase activity. Levels of p53, ATM and tubulin were used as a control.…”

Section: Resultsmentioning

confidence: 99%

“…Although partially effective, harnessing DNA repair deficiencies to induce an enhanced response to therapy and cell death may be hindered by the strong resistance of cancer cells to DNA-damaging agents. There is increasing evidence that ATM also controls metabolic pathways, including mitochondrial respiration, pentose phosphate pathway, and redox homeostasis, all of which enhance metastatic cancer cells survival in nutrient-poor tumor microenvironments 12-15 . Notably, metastatic breast cancer cells rely heavily on multiple metabolic pathways, thus implying that metabolic reprogramming may be key for cancer cells to escape exposure to DNA-damaging agents 16,17 .…”

Section: Introductionmentioning

confidence: 99%

CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors

Liu

Wilson

et al. 2022

Preprint

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Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase ATM using a metabolism-centered CRISPR/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both in vitro and in vivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In the TCGA pan-cancer datasets, we found that ATM levels strongly correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.

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“…It has been demonstrated that PARP activation shifts the metabolic reliance to oxphos, which has been suggested that it is critical for damaged cell survival [ 31 ]. Also, it is well known that metabolism impacts DDR pathway via the regulation of metabolite pools; both glycolysis and glutaminolysis promote DSB repair [ 35 ]. Our results also have shown a decrease in the expression of several genes associated with the pentose phosphate metabolic pathway, which is crucial for nucleotide synthesis and DNA repair.…”

Section: Discussionmentioning

confidence: 99%

Metabolic changes induced by DNA damage in Ramos cells: exploring the role of mTORC1 complex

et al. 2022

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DNA damage induces the activation of many different signals associated with repair or cell death, but it is also connected with physiological events, such as adult neurogenesis and B-cell differentiation. DNA damage induces different signaling pathways, some of them linked to important metabolic changes. The mTORC1 pathway has a central role in the regulation of growth processes and cell division in response to environmental changes and also controls protein synthesis, lipid biogenesis, nucleotide synthesis, and expression of glycolytic genes. Here, we report that double-strand breaks induced with etoposide affect the expression of genes encoding different enzymes associated with specific metabolic pathways in Ramos cells. We also analyzed the role of mTOR signaling, demonstrating that doublestrand breaks induce downregulation of mTOR signaling. Specific inhibition of mTORC1 using rapamycin also induced changes in the expression of metabolic genes. Finally, we demonstrated that DNA damage and rapamycin can regulate glucose uptake. In summary, our findings show that etoposide and rapamycin affect the expression of metabolic genes as well as apoptotic and proliferation markers in Ramos cells, increasing our understanding of cancer metabolism. Double-strand breaks (DSB) are considered among the most cytotoxic damage on the DNA, inducing an essential set of molecular mechanisms to prevent and repair these breaks. The DSB induce the DNA damage response (DDR), which promotes cell cycle arrest, DNA repair mechanisms, and even induces apoptosis and cellular senescence [1]. Interestingly, this DNA repair machinery can be induced in different cells in an intentional and calculated way to generate genetic modification with diverse functionalities, such as neural development, and adult neurogenesis. Specifically, in B cells, the DDR induces B-cell differentiation [2,3], Abbreviations 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; ACSL3, acyl-CoA synthetase for long-chain fatty acids of family 3;

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Genomic instability and metabolism in cancer

Cited by 35 publications

References 101 publications

Mitochondrial control of inflammation

Mitochondrial control of inflammation

CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors

Metabolic changes induced by DNA damage in Ramos cells: exploring the role of mTORC1 complex

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