MYC sensitises cells to apoptosis by driving energetic demand

Edwards-Hicks, Joy; Su, Huizhong; Mangolini, Maurizio; Yoneten, Kubra K; Wills, Jimi; Blanco, Giovanny Rodriguez; Young, Christine; Cho, Kevin; Barker, Heather; Muir, Morwenna; Guerrieri, Ania Naila; Li, Xuefeng; White, Robert L.; Manasterski, Piotr; Mandrou, Elena; Wills, Karen L H; Chen, Jingyu; Abraham, Emily; Sateri, Kianoosh; Qian, Bin‐Zhi; Bankhead, Peter; Arends, Mark J.; Gammoh, Noor; Kriegsheim, Alex von; Patti, Gary J.; Sims, Andrew H.; Acosta, Juan Carlos; Brunton, Valerie G.; Kranc, Kamil R.; Christophorou, Maria A.; Pearce, Erika L.; Ringshausen, Ingo; Finch, Andrew J.

doi:10.1038/s41467-022-32368-z

Cited by 16 publications

(17 citation statements)

References 58 publications

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“…20 In addition to its oncogene function, c-Myc can also cause imbalance of intracellular metabolism/energy supply and demand, making cells sensitive to apoptosis. 37 Overexpression of c-Myc can make cells more dependent on glutamine and mitochondrial oxidative metabolism. 37 In our study, upregulation of c-Myc or c-Jun may lead to the dependence of Shp2 deletion cells on glutamine.…”

Section: Discussionmentioning

confidence: 99%

“…37 Overexpression of c-Myc can make cells more dependent on glutamine and mitochondrial oxidative metabolism. 37 In our study, upregulation of c-Myc or c-Jun may lead to the dependence of Shp2 deletion cells on glutamine.…”

Section: Discussionmentioning

confidence: 99%

“…c‐Jun also promotes GLS1 expression and drives cellular dependence on the glutaminase reaction 20 . In addition to its oncogene function, c‐Myc can also cause imbalance of intracellular metabolism/energy supply and demand, making cells sensitive to apoptosis 37 . Overexpression of c‐Myc can make cells more dependent on glutamine and mitochondrial oxidative metabolism 37 .…”

Section: Discussionmentioning

confidence: 99%

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Deletion of the tyrosine phosphatase Shp2 in cervical cancer cells promotes reprogramming of glutamine metabolism

Gao

Kang

et al. 2023

The FASEB Journal

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Shp2 is a nonreceptor protein tyrosine phosphatase that is overexpressed in cervical cancer. However, the role of Shp2 in the regulation of cervical cancer metabolism and tumorigenesis is unclear. EGFR signaling pathways are commonly dysregulated in cervical cancer. We showed that Shp2 knockout in cervical cancer cells decreased EGFR expression and downregulated downstream RAS–ERK activation. Although AKT was activated in Shp2 knockout cells, inhibition of AKT activation could not make cells more sensitive to death. Shp2 depletion inhibited cervical cancer cell proliferation and reduced tumor growth in a xenograft mouse model. 1H NMR spectroscopic analysis showed that glutamine, glutamate, succinate, creatine, glutathione, and UDP‐GlcNAc were significantly changed in Shp2 knockout cells. The intracellular glutamine level was higher in Shp2 knockout cells than in control cells. Further analysis demonstrated that Shp2 knockout promoted glutaminolysis and glutathione production by up‐regulating the glutamine metabolism‐related genes such as glutaminase (GLS). However, inhibition of GLS did not always make cells sensitive to death, which was dependent on glucose concentration. The level of oxidative phosphorylation was significantly increased, accompanied by an increased generation of reactive oxygen species in Shp2 knockout cells. Shp2 deficiency increased c‐Myc and c‐Jun expression, which may be related to the upregulation of glutamine metabolism. These findings suggested that Shp2 regulates cervical cancer proliferation, glutamine metabolism, and tumorigenicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Deletion of the tyrosine phosphatase Shp2 in cervical cancer cells promotes reprogramming of glutamine metabolism

Gao

Kang

et al. 2023

The FASEB Journal

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“…Glutamine converts into α-ketoglutarate which drives the TCA cycle and synthesizes intermediates for other metabolic tracers and anabolic growth. In MYC-driven cancers, glutamine deletion impairs the TCA cycle and inhibits cancer cell viability in an energetic-demand mechanism ( Edwards-Hicks et al, 2022 ). Instead, in T cells, the inhibition of glutamine metabolism focuses T cell adaption to glycolytic strategy and promotes their proliferation and effector differentiation ( Leone et al, 2019 ).…”

Section: Targeting Lactate Generation and Transportation For Immunoth...mentioning

confidence: 99%

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

Chu

Tian

Yang

et al. 2022

Front. Cell Dev. Biol.

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Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development.

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“…6). However, recent studies suggested that YAP can promote both tumor invasion, migration and apoptosis 39,40 . While the former happens in a TEAD-dependent manner leading to the activation and transcription of AXL (a receptor tyrosine kinase), Gli2 (Glioma-Associated Oncogene Family Zinc Finger 2), and VIM (Vimentin), the later occurs due to Myc overexpression.…”

mentioning

confidence: 99%

Methotrexate-modulated talin-dynamics drives cellular mechanical phenotypes via YAP signaling

Chowdhury

Dhabal

Bhatt

et al. 2023

Preprint

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Methotrexate is a well-known antineoplastic drug used to prevent cancer aggravation. Despite being a targeted therapeutic approach, its administration comes with the risk of cancer recurrence, plausibly through its proven off-target effect on focal adhesions. Since FA dynamics is dependent on force transmission through its constituent proteins, including talin, methotrexate might affect the mechanical activity of these proteins. Here we have combined single-molecule studies, computational dynamics, cell-based assays, and genomic analysis to unveil the focal adhesion-regulating role of methotrexate central to its effect on talin dynamics and downstream pathways. Interestingly, our single-molecule force spectroscopic study shows that methotrexate modulates the bimodal force distribution of talin in a concentration-dependent manner. Steered molecular dynamics reveal that methotrexate-talin interactions alter talin mechanical stability exposing their vinculin binding sites. Finally, we found that methotrexate-regulated talin-dynamics remodel cancer cell mechanical phenotypes like cell polarity, adhesion, and migration by regulating talin-vinculin association-mediated YAP signaling. These results further correlate with genomic analysis of methotrexate-treated patients, demonstrating its clinical importance. Taken together, these findings disseminate the effects of methotrexate-modulated mechanosensitivity of adhesion proteins on cellular events.

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MYC sensitises cells to apoptosis by driving energetic demand

Cited by 16 publications

References 58 publications

Deletion of the tyrosine phosphatase Shp2 in cervical cancer cells promotes reprogramming of glutamine metabolism

Deletion of the tyrosine phosphatase Shp2 in cervical cancer cells promotes reprogramming of glutamine metabolism

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

Methotrexate-modulated talin-dynamics drives cellular mechanical phenotypes via YAP signaling

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