4EBP1/2 support tumorigenicity and cell survival during energetic stress by translationally regulating fatty acid synthesis

Energetic stress compels cells to evolve adaptive mechanisms to maintain homeostasis. Here, we report that the negative regulators of mRNA translation initiation eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) are essential to promote the survival of mammalian cells and budding yeast under glucose starvation. Functionally, 4EBP1/2 inhibit fatty acid synthesis upon energetic stress via repression of Acetyl-CoA Carboxylase Alpha (ACACA) mRNA translation, sparing NADPH, to maintain intracellular redox balance. This has important relevance in cancers, as we uncovered that oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACACA expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 (encoding 4EBP1) expression is associated with poor outcomes in several cancer types, including glioma. Our data reveal that 4EBP1/2 are conserved mediators of the survival response to energetic stress which are exploited by cancer cells for metabolic adaptation.

[1]  G. Reifenberger,et al.  Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) expression in glioblastoma is driven by ETS1- and MYBL2-dependent transcriptional activation , 2022, Cell death discovery.

[2]  G. Reifenberger,et al.  EIF4EBP1 is transcriptionally upregulated by MYCN and associates with poor prognosis in neuroblastoma , 2021, bioRxiv.

[3]  R. Shaw,et al.  AMPK: restoring metabolic homeostasis over space and time. , 2021, Molecular cell.

[4]  G. Wagner,et al.  Deep computational analysis details dysregulation of eukaryotic translation initiation complex eIF4F in human cancers. , 2021, Cell systems.

[5]  Manolis Kellis,et al.  Metabolic resilience is encoded in genome plasticity , 2021, bioRxiv.

[6]  A. Burlingame,et al.  The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity , 2021, Nature Metabolism.

[7]  E. Kohmura,et al.  Glioma cells require one-carbon metabolism to survive glutamine starvation , 2021, Acta Neuropathologica Communications.

[8]  D. Sabatini,et al.  Dihydroxyacetone phosphate signals glucose availability to mTORC1 , 2020, Nature Metabolism.

[9]  B. Rotblat,et al.  How does mTOR sense glucose starvation? AMPK is the usual suspect , 2020, Cell Death Discovery.

[10]  D. Sabatini,et al.  mTOR at the nexus of nutrition, growth, ageing and disease , 2020, Nature Reviews Molecular Cell Biology.

[11]  Ji Ae Song,et al.  Glucose-dependent control of leucine metabolism by leucyl-tRNA synthetase 1 , 2019, Science.

[12]  T. Shlomi,et al.  Intra-Tumoral Metabolic Zonation and Resultant Phenotypic Diversification Are Dictated by Blood Vessel Proximity. , 2019, Cell metabolism.

[13]  Z. Ignatova,et al.  ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumor progression , 2019, Nature Cell Biology.

[14]  S. Lippman,et al.  4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer. , 2019, Cancer research.

[15]  B. Manning,et al.  Molecular logic of mTORC1 signalling as a metabolic rheostat , 2019, Nature Metabolism.

[16]  R. Shaw,et al.  Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras-Dependent Lung Cancer Models. , 2019, Cell metabolism.

[17]  M. V. Vander Heiden,et al.  Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability , 2018, bioRxiv.

[18]  R. Müller,et al.  The Translational Machinery of Human CD4+ T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic Remodeling. , 2018, Cell metabolism.

[19]  M. Weirauch,et al.  AMP Kinase Promotes Glioblastoma Bioenergetics and Tumor Growth , 2018, Nature Cell Biology.

[20]  F. Damiano,et al.  Translational control of human acetyl-CoA carboxylase 1 mRNA is mediated by an internal ribosome entry site in response to ER stress, serum deprivation or hypoxia mimetic CoCl2. , 2018, Biochimica et biophysica acta. Molecular and cell biology of lipids.

[21]  P. Pandolfi,et al.  The mTOR Targets 4E-BP1/2 Restrain Tumor Growth and Promote Hypoxia Tolerance in PTEN-driven Prostate Cancer , 2018, Molecular Cancer Research.

[22]  Sheng-Cai Lin,et al.  AMPK: Sensing Glucose as well as Cellular Energy Status. , 2017, Cell metabolism.

[23]  B. Rotblat,et al.  Puromycin labeling does not allow protein synthesis to be measured in energy-starved cells , 2018, Cell Death & Disease.

[24]  O. Larsson,et al.  Polysome-profiling in small tissue samples , 2017, bioRxiv.

[25]  Davide Ruggero,et al.  New frontiers in translational control of the cancer genome , 2016, Nature Reviews Cancer.

[26]  N. Hay,et al.  Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? , 2016, Nature Reviews Cancer.

[27]  B. Rotblat,et al.  Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1): a master regulator of mRNA translation involved in tumorigenesis , 2016, Oncogene.

[28]  T. Tokuyasu,et al.  Differential Requirements for eIF4E Dose in Normal Development and Cancer , 2015, Cell.

[29]  P. Sorensen,et al.  Stress-mediated translational control in cancer cells. , 2015, Biochimica et biophysica acta.

[30]  L. Cantley,et al.  Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain. , 2015, Cancer research.

[31]  E. E. Vincent,et al.  The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. , 2015, Cancer letters.

[32]  T. Shlomi,et al.  Quantitative flux analysis reveals folate-dependent NADPH production , 2014, Nature.

[33]  N. Sonenberg,et al.  mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. , 2013, Cell metabolism.

[34]  Andrew E. Sloan,et al.  Brain Tumor Initiating Cells Adapt to Restricted Nutrition through Preferential Glucose Uptake , 2013, Nature Neuroscience.

[35]  V. P. Collins,et al.  The eEF2 Kinase Confers Resistance to Nutrient Deprivation by Blocking Translation Elongation , 2013, Cell.

[36]  G. Waldrop,et al.  Complex formation and regulation of Escherichia coli acetyl-CoA carboxylase. , 2013, Biochemistry.

[37]  L. Flohé.  The fairytale of the GSSG/GSH redox potential. , 2013, Biochimica et biophysica acta.

[38]  Navdeep S. Chandel,et al.  AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress , 2012, Nature.

[39]  D. Sabatini,et al.  A unifying model for mTORC1-mediated regulation of mRNA translation , 2012, Nature.

[40]  Nicholas T. Ingolia,et al.  The translational landscape of mTOR signalling steers cancer initiation and metastasis , 2012, Nature.

[41]  P. Sorensen,et al.  The AMPK stress response pathway mediates anoikis resistance through inhibition of mTOR and suppression of protein synthesis , 2011, Cell Death and Differentiation.

[42]  Cristina Muñoz-Pinedo,et al.  Dying for Something to Eat: How Cells Respond to Starvation , 2011 .

[43]  Julian N. Selley,et al.  Identifying eIF4E-binding protein translationally-controlled transcripts reveals links to mRNAs bound by specific PUF proteins , 2010, Nucleic acids research.

[44]  N. Sonenberg,et al.  mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs , 2010, Science.

[45]  Sang Gyun Kim,et al.  Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. , 2010, Molecular cell.

[46]  S. Formenti,et al.  Translational control in cancer , 2010, Nature Reviews Cancer.

[47]  N. Sonenberg,et al.  p53-dependent translational control of senescence and transformation via 4E-BPs. , 2009, Cancer cell.

[48]  Subhash D. Katewa,et al.  4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila , 2009, Cell.

[49]  Hanna Y. Irie,et al.  Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment , 2009, Nature.

[50]  H. Dvorak,et al.  Why are tumour blood vessels abnormal and why is it important to know? , 2009, British Journal of Cancer.

[51]  A. Hinnebusch,et al.  Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets , 2009, Cell.

[52]  H. Yee,et al.  A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. , 2007, Molecular cell.

[53]  A. Teleman,et al.  4E-BP functions as a metabolic brake used under stress conditions but not during normal growth. , 2005, Genes & development.

[54]  N. Sonenberg,et al.  Starvation and oxidative stress resistance in Drosophila are mediated through the eIF4E-binding protein, d4E-BP. , 2005, Genes & development.

[55]  A. Goldberg,et al.  Patterns of gene expression in atrophying skeletal muscles: response to food deprivation , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[56]  B. Spiegelman,et al.  Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1 , 2001, Nature Medicine.

[57]  A. Gingras,et al.  4E-BP3, a New Member of the Eukaryotic Initiation Factor 4E-binding Protein Family* , 1998, The Journal of Biological Chemistry.

[58]  F. Buttgereit,et al.  A hierarchy of ATP-consuming processes in mammalian cells. , 1995, The Biochemical journal.

[59]  N. Sonenberg,et al.  The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins , 1995, Molecular and cellular biology.

[60]  A. Gingras,et al.  Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function , 1994, Nature.

[61]  L. Fellows,et al.  Rapid changes in extracellular glucose levels and blood flow in the striatum of the freely moving rat , 1993, Brain Research.

[62]  N. Sonenberg,et al.  Interactions of the eIF-4F subunits in the yeast Saccharomyces cerevisiae. , 1992, The Journal of biological chemistry.

[63]  R. Gruetter,et al.  Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[64]  P. Gullino,et al.  THE INTERSTITIAL FLUID OF SOLID TUMORS. , 1964, Cancer research.