ATF4-induced warburg metabolism drives over-proliferation in Drosophila
Open accessAbstract
The mitochondrial electron transport chain (ETC) enables essential metabolic reactions; nonetheless, the cellular responses to defects in mitochondria and the modulation of signaling pathway outputs are not understood. We show that Notch signaling and ETC attenuation via knockdown of COX7a induces massive over-proliferation. The tumor-like growth is caused by a transcriptional response through the eIF2α-kinase PERK and ATF4, which activates the expression of metabolic enzymes, nutrient transporters, and mitochondrial chaperones. We find this stress adaptation to be beneficial for progenitor cell fitness, as it renders cells sensitive to proliferation induced by the Notch signaling pathway. Intriguingly, over-proliferation is not caused by transcriptional cooperation of Notch and ATF4, but it is mediated in part by pH changes resulting from the Warburg metabolism induced by ETC attenuation. Our results suggest that ETC function is monitored by the PERK-ATF4 pathway, which can be hijacked by growth-promoting signaling pathways, leading to oncogenic pathway activity.
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Transcription factors c-Myc and ATF4 are two master-regulators of glycolysis, respiration, and one-carbon metabolism.
“Transcription factors c-Myc and ATF4 are two master-regulators of glycolysis, respiration, and one-carbon metabolism [44,45,46,49].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [49]
Cites
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890 · see citing works
A Threshold Selection Method from Gray-Level Histograms
Otsu, N. (1979) · IEEE Transactions on Systems Man and Cybernetics · doi:10.1109/tsmc.1979.4310076 · Cited by 43,748 · see citing works
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088 · see citing works
Reactive oxygen species in cancer
Liou, G., & Störz, P. (2010) · Free Radical Research · doi:10.3109/10715761003667554 · Cited by 3,394 · see citing works
A pathology atlas of the human cancer transcriptome
Uhlen, M., Zhang, C., Lee, S., Sjöstedt, E., Fagerberg, L., Bidkhori, G., Benfeitas, R., Arif, M., Liu, Z., Edfors, F., et al. (2017) · Science · doi:10.1126/science.aan2507 · Cited by 3,371 · see citing works
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
Harding, H. P., Zhang, Y., & Ron, D. (1999) · Nature · doi:10.1038/16729 · Cited by 3,310 · see citing works
Regulated Translation Initiation Controls Stress-Induced Gene Expression in Mammalian Cells
Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R. C., Schapira, M., & Ron, D. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00108-8 · Cited by 3,281 · see citing works
Tumor Hypoxia: Definitions and Current Clinical, Biologic, and Molecular Aspects
Hockel, M., & Vaupel, P. (2001) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/93.4.266 · Cited by 2,662 · see citing works
Notch signalling: a simple pathway becomes complex
Bray, S. J. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2009 · Cited by 2,620 · see citing works
Dysregulated pH: a perfect storm for cancer progression
Webb, B. A., Chimenti, M. S., Jacobson, M. P., & Barber, D. L. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3110 · Cited by 2,246 · see citing works
Zinszner, H., Kuroda, M., Wang, X., Batchvarova, N., Lightfoot, R. T., Remotti, H. E., Stevens, J. L., & Ron, D. (1998) · Genes & Development · doi:10.1101/gad.12.7.982 · Cited by 1,996 · see citing works
Mitochondrial reactive oxygen species trigger hypoxia-induced transcription
Chandel, N. S., Maltepe, E., Goldwasser, E., Mathieu, C. E., Simon, M. C., & Schumacker, P. T. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.20.11715 · Cited by 1,926 · see citing works
Birsoy, K., Wang, T., Chen, W. W., Freinkman, E., Abu-Remaileh, M., & Sabatini, D. M. (2015) · Cell · doi:10.1016/j.cell.2015.07.016 · Cited by 1,388 · see citing works
Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells
Sullivan, L. B., Gui, D. Y., Hosios, A. M., Bush, L. N., Freinkman, E., & Vander Heiden, M. G. (2015) · Cell · doi:10.1016/j.cell.2015.07.017 · Cited by 1,173 · see citing works
Tumor suppressors and cell metabolism: a recipe for cancer growth
Jones, R. G., & Thompson, C. B. (2009) · Genes & Development · doi:10.1101/gad.1756509 · Cited by 1,085 · see citing works
Expression of baculovirus P35 prevents cell death in Drosophila
Hay, B. A., Wolff, T., & Rubin, G. M. (1994) · Development · doi:10.1242/dev.120.8.2121 · Cited by 1,066 · see citing works
Yamamoto, K., Sato, T., Matsui, T., Sato, M., Okada, T., Yoshida, H., Harada, A., & Mori, K. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.07.018 · Cited by 1,056 · see citing works
Mitochondrial Import Efficiency of ATFS-1 Regulates Mitochondrial UPR Activation
Nargund, A. M., Pellegrino, M., Fiorese, C. J., Baker, B. M., & Haynes, C. M. (2012) · Science · doi:10.1126/science.1223560 · Cited by 1,027 · see citing works
The Metabolism of Carcinoma Cells
Warburg, O. H. (1925) · The Journal of Cancer Research · doi:10.1158/jcr.1925.148 · Cited by 1,005 · see citing works
iRegulon: From a Gene List to a Gene Regulatory Network Using Large Motif and Track Collections
Janky, R., Verfaillie, A., Imrichová, H., Van de Sande, B., Standaert, L., Christiaens, V., Hulselmans, G., Herten, K., Naval Sanchez, M., Potier, D., et al. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003731 · Cited by 900 · see citing works
Hypoxia signalling through mTOR and the unfolded protein response in cancer
Wouters, B. G., & Koritzinsky, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2501 · Cited by 894 · see citing works
Quirós, P. M., Prado, M. A., Zamboni, N., D’Amico, D., Williams, R. W., Finley, D., Gygi, S. P., & Auwerx, J. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201702058 · Cited by 832 · see citing works
ER stress‐regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
Bi, M., Naczki, C., Koritzinsky, M., Fels, D. R., Blais, J. D., Hu, N., Harding, H. P., Novoa, I., Varia, M. A., Raleigh, J. A., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600777 · Cited by 732 · see citing works
Ye, J., Kumanova, M., Hart, L. S., Sloane, K. L., Zhang, H., Panis, D. N. D., Bobrovnikova-Marjon, E. V., Diehl, J. A., Ron, D., & Koumenis, C. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.81 · Cited by 709 · see citing works
The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR
Fiorese, C. J., Schulz, A. M., Lin, Y., Rosin, N., Pellegrino, M. W., & Haynes, C. M. (2016) · Current Biology · doi:10.1016/j.cub.2016.06.002 · Cited by 672 · see citing works
ATF4-dependent transcription mediates signaling of amino acid limitation
Kilberg, M. S., Shan, J., & Su, N. Y. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.05.008 · Cited by 595 · see citing works
Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations
Capon, D. J., Seeburg, P. H., McGrath, J. P., Hayflick, J. S., Edman, U., Levinson, A. D., & Goeddel, D. V. (1983) · Nature · doi:10.1038/304507a0 · Cited by 551 · see citing works
The chemistry, physiology and pathology of pH in cancer
Swietach, P., Vaughan‐Jones, R. D., Harris, A. L., & Hulı́ková, A. (2014) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2013.0099 · Cited by 542 · see citing works
Mitochondrial dysfunction remodels one-carbon metabolism in human cells
Bao, X. R., Ong, S., Goldberger, O., Peng, J., Sharma, R., Thompson, D. A., Vafai, S. B., Cox, A. G., Marutani, E., Ichinose, F., et al. (2016) · eLife · doi:10.7554/elife.10575 · Cited by 439 · see citing works
Uber den Stoffwechsel der Karzinomezellen
Warburg, O. (1924) · Medical Entomology and Zoology · Cited by 401 · see citing works
San Martín, A., Ceballo, S., Ruminot, I., Lerchundi, R., Frommer, W. B., & Barros, L. F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057712 · Cited by 361 · see citing works
BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation
Raffel, S., Falcone, M., Kneisel, N., Hansson, J., Wang, W., Lutz, C., Bullinger, L., Poschet, G., Nonnenmacher, Y., Barnert, A., et al. (2017) · Nature · doi:10.1038/nature24294 · Cited by 354 · see citing works
Abe, H. (2000) · PubMed · Cited by 350 · see citing works
Takanaga, H., Chaudhuri, B., & Frommer, W. B. (2008) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2007.11.015 · Cited by 333 · see citing works
A versatile platform for creating a comprehensive UAS-ORFeome library in Drosophila
Bischof, J., Björklund, M., Furger, E., Schertel, C., Taipale, J., & Basler, K. (2013) · Development · doi:10.1242/dev.088757 · Cited by 325 · see citing works
Unfolded protein response in a Drosophila model for retinal degeneration
Ryoo, H. D., Domingos, P. M., Kang, M., & Steller, H. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601477 · Cited by 292 · see citing works
Avérous, J., Bruhat, A., Jousse, C., Carraro, V., Thiel, G., & Fafournoux, P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311862200 · Cited by 279 · see citing works
A dorsal/ventral boundary established by Notch controls growth and polarity in the Drosophila eye
Domínguez, M., & de Celis, J. F. (1998) · Nature · doi:10.1038/24402 · Cited by 254 · see citing works
Chatterjee, N., & Bohmann, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034063 · Cited by 254 · see citing works
Wirtz, M. (2004) · Journal of Experimental Botany · doi:10.1093/jxb/erh201 · Cited by 222 · see citing works
Networks of bZIP Protein-Protein Interactions Diversified Over a Billion Years of Evolution
Reinke, A. W., Baek, J., Ashenberg, O., & Keating, A. E. (2013) · Science · doi:10.1126/science.1233465 · Cited by 207 · see citing works
Celardo, I., Costa, A. C., Lehmann, S., Jones, C., Wood, N. W., Mencacci, N. E., Mallucci, G. R., Loh, S. H. Y., & Martins, L. M. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.173 · Cited by 181 · see citing works
Ameri, K., Lewis, C. E., Raida, M. K., Sowter, H., Hai, T., & Harris, A. L. (2003) · Blood · doi:10.1182/blood-2003-06-1859 · Cited by 178 · see citing works
Schönichen, A., Webb, B. A., Jacobson, M. P., & Barber, D. L. (2013) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-050511-102349 · Cited by 162 · see citing works
Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival
Pathria, G., Scott, D. A., Feng, Y., Lee, J. S., Fujita, Y., Zhang, G., Sahu, A. D., Ruppin, E., Herlyn, M., Osterman, A. L., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201899735 · Cited by 157 · see citing works
Fast Calcium Signals inDrosophilaMotor Neuron Terminals
Macleod, G. T., Hegström-Wojtowicz, M., Charlton, M. P., & Atwood, H. L. (2002) · Journal of Neurophysiology · doi:10.1152/jn.00515.2002 · Cited by 153 · see citing works
Goberdhan, D. C. I., Meredith, D., Boyd, C. A. R., & WILSON, C. G. (2005) · Development · doi:10.1242/dev.01821 · Cited by 151 · see citing works
Targeting the ATF4 pathway in cancer therapy
Singleton, D. C., & Harris, A. L. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.728207 · Cited by 130 · see citing works
Cancer RNA-Seq Nexus: a database of phenotype-specific transcriptome profiling in cancer cells
Li, J., Sun, C.-H., Li, W., Chao, R.-F., Huang, C., Zhou, X. J., & Liu, C.-C. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1282 · Cited by 109 · see citing works
Huggins, C. J., Mayekar, M. K., Martín, N. C. R., Saylor, K. L., Gonit, M., Jailwala, P., Kasoji, M., Haines, D. C., Quiñones, O. A., & Johnson, P. F. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00911-15 · Cited by 106 · see citing works
Lee, J.-I., Dominy, J. E., Sikalidis, A. K., et al. (2008) · Physiological Genomics · doi:10.1152/physiolgenomics.00263.2007 · Cited by 103 · see citing works
4E-BP is a target of the GCN2–ATF4 pathway during Drosophila development and aging
Kang, M., Vasudevan, D., Kang, K., Kim, K., Park, J.-E., Zhang, N., Zeng, X., Neubert, T. A., Marr, M. T., & Ryoo, H. D. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201511073 · Cited by 102 · see citing works
In vivo genetic dissection of tumor growth and the Warburg effect
Wang, C., Purkayastha, A., Jones, K. T., Thaker, S. K., & Banerjee, U. K. (2016) · eLife · doi:10.7554/elife.18126 · Cited by 90 · see citing works
dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective
Celardo, I., Lehmann, S., Costa, A. C. O., Loh, S. H. Y., & Martins, L. M. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2016.158 · Cited by 77 · see citing works
Volkenhoff, A., Hirrlinger, J., Kappel, J. M., Klämbt, C., & Schirmeier, S. (2017) · Journal of Insect Physiology · doi:10.1016/j.jinsphys.2017.07.010 · Cited by 77 · see citing works
Self-citationAMPK and GCN2–ATF4 signal the repression of mitochondria in colon cancer cells
Martínez‐Reyes, I., Sánchez‐Aragó, M., & Cuezva, J. M. (2012) · Biochemical Journal · doi:10.1042/bj20111829 · Cited by 64 · see citing works
Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids
Weger, B. D., Weger, M., Görling, B., Schink, A., Gobet, C., Keime, C., Poschet, G., Jost, B., Krone, N. P., Hell, R., et al. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006512 · Cited by 59 · see citing works
Lee, J., Oney, M., Frizzell, K., Phadnis, N., & Hollien, J. (2015) · G3 Genes Genomes Genetics · doi:10.1534/g3.115.017269 · Cited by 53 · see citing works
Zhai, Z., Ha, N., Papagiannouli, F., Hamacher‐Brady, A., Brady, N. R., Sorge, S., Bezdan, D., & Lohmann, I. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002582 · Cited by 47 · see citing works
Self-citationLactate transport in freshly isolated human fetal retinal pigment epithelium.
la Cour, M., Lin, H., Kenyon, E., & Miller, S. S. (1994) · PubMed · Cited by 45 · see citing works
Warburg Effect Metabolism Drives Neoplasia in a Drosophila Genetic Model of Epithelial Cancer
Eichenlaub, T., Villadsen, R., Freitas, F. C. D. P., Andrējeva, D., Aldana, B. I., Nguyen, T., PETERSEN, O. W., Gorodkin, J., Herranz, H., & Cohen, S. M. (2018) · Current Biology · doi:10.1016/j.cub.2018.08.035 · Cited by 42 · see citing works
Long Term Ex Vivo Culture and Live Imaging of Drosophila Larval Imaginal Discs
Tsao, C.-K., Ku, H.-Y., Lee, Y.-M., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163744 · Cited by 41 · see citing works
Nowak, K., Seisenbacher, G., Hafen, E., & Stocker, H. (2013) · eLife · doi:10.7554/elife.00380 · Cited by 38 · see citing works
Dolan, E., Saunders, B., Dantas, W. S., Murai, I. H., Roschel, H., Artioli, G. G., Harris, R. C., Bicudo, J. E. P. W., Sale, C., & Gualano, B. (2018) · Scientific Reports · doi:10.1038/s41598-018-32636-3 · Cited by 30 · see citing works
Uran, S. R., Landmark, K. E., Hjellum, G., et al. (2007) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2007.04.001 · Cited by 25 · see citing works
Rossano, A. J., Kato, A., Minard, K. I., Romero, M. F., & Macleod, G. T. (2016) · The Journal of Physiology · doi:10.1113/jp273105 · Cited by 25 · see citing works
Gándara, L., Durrieu, L., Behrensen, C., & Wappner, P. (2019) · Scientific Reports · doi:10.1038/s41598-019-56446-3 · Cited by 25 · see citing works
The Alternative Oxidase AOX Does Not Rescue the Phenotype oftko25tMutant Flies
Kemppainen, K. K., Kemppainen, E., & Jacobs, H. T. (2014) · G3 Genes Genomes Genetics · doi:10.1534/g3.114.013946 · Cited by 23 · see citing works
WEADE: A workflow for enrichment analysis and data exploration
Trost, N., Rempel, E., Ermakova, O. V., Tamirisa, S., Pârcălăbescu, L., Boutros, M., Lohmann, J. U., & Lohmann, I. (2018) · PLoS ONE · doi:10.1371/journal.pone.0204016 · Cited by 6 · see citing works
Self-citationIntracellular pH controls Wnt signaling downstream of glycolysis in the vertebrate embryoPreprint
Oginuma, M., Harima, Y., Xiong, F., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/481259 · Cited by 3 · see citing works
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Floc'hlay, S., Balaji, R., Stanković, D., Christiaens, V. M., Bravo González-Blas, C., De Winter, S., Hulselmans, G. J., De Waegeneer, M., Quan, X., Koldere, D., et al. (2023) · eLife · doi:10.7554/elife.81173 · Cited by 27 · see citing works
Shuvalov, O., Kirdeeva, Y., Fefilova, E., Netsvetay, S., Zorin, M., Vlasova, Y., Fedorova, O., Daks, A., Parfenyev, S., & Barlev, N. (2023) · Metabolites · doi:10.3390/metabo13050656 · Cited by 21 · see citing works
- Authors
- Sorge, S., Theelke, J., Yildirim, K., Hertenstein, H., McMullen, E., Müller, S., Altbürger, C., Schirmeier, S., & Lohmann, I.
- Affiliations
- Heidelberg University (DE)
- University of Münster (DE)
- University of Freiburg (DE)
- Corresponding author
- Lohmann, Ingrid
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 31
- Issue
- 7
- Pages
- 107659
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W3026560547
- Cited by
- 44
- References
- 70
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 7 · 2023: 10 · 2022: 7 · 2021: 4
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Deutsche Forschungsgemeinschaft (Excellence Cluster CellNetworks, ZUK 40/2010-3009262, CellNetworks/EcTop6)
- Universität Heidelberg
- Heidelberg Biosciences International Graduate School
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- ATF4, mitochondrial electron transport chain, Notch signaling, PERK-eIF2α pathway, Drosophila, mitochondrial stress response, pH change
- MeSH terms
- Warburg Effect, Oncologic, Animals, Cells, Cultured, Electron Transport Complex IV, Drosophila, Drosophila melanogaster, Electron Transport, Female, Male, Stem Cells, Transcription Factors, eIF-2 Kinase, Drosophila Proteins, Animals, Genetically Modified, Cell Proliferation, Activating Transcription Factor 4, Receptors, Notch
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