ATF4-Induced Warburg Metabolism Drives Over-Proliferation in Drosophila

Sorge, Sebastian; Theelke, Jonas; Yildirim, Kerem; Hertenstein, Helen; McMullen, Ellen; Müller, Stephan; Altbürger, Christian; Schirmeier, Stefanie; Lohmann, Ingrid

doi:10.1016/j.celrep.2020.107659

Cited by 25 publications

(20 citation statements)

References 70 publications

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“…To study the roles of LDH in tumor growth in Drosophila, researchers have used genetic manipulations to modulate Ldh gene expression. Overexpression of Ldh can transform Egfr-induced hyperplasia into neoplasia, as seen with other hyperplasia models, including those driven by Notch and Yki activation (Eichenlaub et al, 2018;Sorge et al, 2020). Genetic inhibition of LDH, however, has varying effects on tumor progression (Fig.…”

Section: Ldh Drives Neoplastic Transformation In Certain Tumor Typesmentioning

confidence: 91%

“…Increased proliferation (Go et al, 1998) LDH/lactate unchanged (Gándara et al, 2019;Sorge et al, 2020); LDH downregulated (Ho et al, 2015); LDH upregulated (Slaninova et al, 2016) TCA cycle genes downregulated (Slaninova et al, 2016) n/d…”

Section: The Warburg Effectmentioning

confidence: 99%

“…Disc overgrowths caused by activated Yki and Ras exhibit weak and moderate LDH upregulation, respectively ( Wang et al, 2016 ). Unchanged, increased and decreased levels of LDH/lactate have been reported in hyperplastic discs caused by activation of Notch ( Gándara et al, 2019 ; Ho et al, 2015 ; Slaninova et al, 2016 ; Sorge et al, 2020 ). Such an inconsistency could be explained by the degree and extent of Notch activation, or might be a result of interactions with local signaling pathways.…”

Section: The Warburg Effectmentioning

confidence: 99%

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Metabolic reprogramming in cancer: mechanistic insights from Drosophila

Wong

Verheyen

2021

Disease Models &Amp; Mechanisms

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Cancer cells constantly reprogram their metabolism as the disease progresses. However, our understanding of the metabolic complexity of cancer remains incomplete. Extensive research in the fruit fly Drosophila has established numerous tumor models ranging from hyperplasia to neoplasia. These fly tumor models exhibit a broad range of metabolic profiles and varying nutrient sensitivity. Genetic studies show that fly tumors can use various alternative strategies, such as feedback circuits and nutrient-sensing machinery, to acquire and consolidate distinct metabolic profiles. These studies not only provide fresh insights into the causes and functional relevance of metabolic reprogramming but also identify metabolic vulnerabilities as potential targets for cancer therapy. Here, we review the conceptual advances in cancer metabolism derived from comparing and contrasting the metabolic profiles of fly tumor models, with a particular focus on the Warburg effect, mitochondrial metabolism, and the links between diet and cancer.

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Section: Ldh Drives Neoplastic Transformation In Certain Tumor Typesmentioning

confidence: 91%

Section: The Warburg Effectmentioning

confidence: 99%

Section: The Warburg Effectmentioning

confidence: 99%

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Metabolic reprogramming in cancer: mechanistic insights from Drosophila

Wong

Verheyen

2021

Disease Models &Amp; Mechanisms

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“…However, these patients also present mutations in other genes [ 183 ], thereby is still unclear whether the development of the diseases is due to alterations in mitophagy itself or rather a general mitochondrial dysfunction. Alterations in the expression of proteins involved in mitochondrial retrograde signaling (ISR) have also been linked to resistance and tumour growth [ 17 , 73 , 74 , 77 ]. Hence, even though in the recent years new findings have given some clarity in understanding the mitochondrial quality control pathways, some mechanisms underlying mitochondrial homeostasis remain still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Although the involvement of mitochondria was not shown directly in these studies, they offer proof of principle that ISR can induce drug resistance. Recently, ATF4 has also been shown to be oncogenic; in Drosophila , activation of ATF4 induced a Warburg-like phenotype and consequently tumorigenic growth [ 77 ] and in MYC-driven tumours, deletion of ATF4 prolonged survival [ 17 ], indicating that ATF4 is necessary for tumorigenesis. Collectively, although several advances have been made over the recent years in understanding the mitochondrial retrograde response in several organisms, much remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial quality control: from molecule to organelle

Roca-Portoles

Tait

2021

Cell. Mol. Life Sci.

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Mitochondria are organelles central to myriad cellular processes. To maintain mitochondrial health, various processes co-operate at both the molecular and organelle level. At the molecular level, mitochondria can sense imbalances in their homeostasis and adapt to these by signaling to the nucleus. This mito-nuclear communication leads to the expression of nuclear stress response genes. Upon external stimuli, mitochondria can also alter their morphology accordingly, by inducing fission or fusion. In an extreme situation, mitochondria are degraded by mitophagy. Adequate function and regulation of these mitochondrial quality control pathways are crucial for cellular homeostasis. As we discuss, alterations in these processes have been linked to several pathologies including neurodegenerative diseases and cancer.

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Redox regulation of UPR signalling and mitochondrial ER contact sites

Casas-Martinez,

Samali,

McDonagh

2024

Cell. Mol. Life Sci.

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Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.

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ATF4-Induced Warburg Metabolism Drives Over-Proliferation in Drosophila

Cited by 25 publications

References 70 publications

Metabolic reprogramming in cancer: mechanistic insights from Drosophila

Metabolic reprogramming in cancer: mechanistic insights from Drosophila

Mitochondrial quality control: from molecule to organelle

Redox regulation of UPR signalling and mitochondrial ER contact sites

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