IRE1&agr; RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers

Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here, we show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the inositol-requiring enzyme 1&agr; (IRE1&agr;)/X-box binding protein 1 (XBP1) pathway through multiple molecular mechanisms in a variety of c-Myc– and N-Myc–dependent cancers. In particular, Myc-overexpressing cells require IRE1&agr;/XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity. Pharmacological and genetic XBP1 inhibition induces Myc-dependent apoptosis, which is alleviated by exogenous unsaturated fatty acids. Of note, SCD1 inhibition phenocopies IRE1&agr; RNase activity suppression in vivo. Furthermore, IRE1&agr; inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc–overexpressing Burkitt’s lymphoma, suggesting that inhibiting the IRE1&agr;/XBP1 pathway is a useful general strategy for treatment of Myc-driven cancers.

[1]  A. P. Kolesnichenko,et al.  Acute lung injury , 2020, Intensive Care Medicine.

[2]  G. Rabinovich,et al.  IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity , 2018, Nature.

[3]  Kuan-Der Lee,et al.  ER stress‐related ATF6 upregulates CIP2A and contributes to poor prognosis of colon cancer , 2018, Molecular oncology.

[4]  Sean M. Hartig,et al.  Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer , 2018, The Journal of clinical investigation.

[5]  D. Sabatini,et al.  mTOR Signaling in Growth, Metabolism, and Disease , 2017, Cell.

[6]  Wei Wei,et al.  Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation , 2017, World journal of gastroenterology.

[7]  L. Chin,et al.  Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer , 2017, Nature.

[8]  Lizhi Song,et al.  A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability , 2017, Nature Communications.

[9]  J. Joyce,et al.  STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1α Activation. , 2016, Cell reports.

[10]  A. Califano,et al.  HAUSP deubiquitinated and stabilizes N-Myc in neuroblastoma , 2016, Nature Medicine.

[11]  C. Hetz,et al.  Endoplasmic Reticulum Stress and the Hallmarks of Cancer. , 2016, Trends in cancer.

[12]  A. Papavassiliou,et al.  XBP1: A Pivotal Transcriptional Regulator of Glucose and Lipid Metabolism , 2016, Trends in Endocrinology & Metabolism.

[13]  A. Burke,et al.  Update on non-Hodgkin lymphoma in children , 2016 .

[14]  D. Hallahan,et al.  The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma , 2015, Oncotarget.

[15]  S. Kersten,et al.  IRE1α is an endogenous substrate of endoplasmic reticulum-associated degradation , 2015, Nature Cell Biology.

[16]  R. Schreiber,et al.  Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression , 2015, Cell.

[17]  Jian-hua Li,et al.  Spliced XBP1 promotes macrophage survival and autophagy by interacting with Beclin-1. , 2015, Biochemical and biophysical research communications.

[18]  D. Tuveson,et al.  The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1 , 2015, Cell.

[19]  M. Feldman,et al.  ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. , 2015, The Journal of clinical investigation.

[20]  L. Glimcher,et al.  The transcription factor XBP1 is selectively required for eosinophil differentiation , 2015, Nature Immunology.

[21]  Juan R. Cubillos-Ruiz,et al.  ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis , 2015, Cell.

[22]  A. McCallion,et al.  Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. , 2015, The Journal of clinical investigation.

[23]  Brian Keith,et al.  HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma. , 2015, Cancer discovery.

[24]  H. Molly,et al.  Tumor growth in vivo. , 2015 .

[25]  J. Hurley,et al.  Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. , 2015, Cancer cell.

[26]  M. McKeown,et al.  Therapeutic strategies to inhibit MYC. , 2014, Cold Spring Harbor perspectives in medicine.

[27]  R. Kaufman,et al.  The impact of the endoplasmic reticulum protein-folding environment on cancer development , 2014, Nature Reviews Cancer.

[28]  G. Evan,et al.  Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis , 2014, Nature Communications.

[29]  M. Simon,et al.  Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. , 2014, Trends in cell biology.

[30]  R. Tibshirani,et al.  Alteration of the lipid profile in lymphomas induced by MYC overexpression , 2014, Proceedings of the National Academy of Sciences.

[31]  C. Cubitt,et al.  Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. , 2014, The Journal of clinical investigation.

[32]  D. Felsher,et al.  MYC activation is a hallmark of cancer initiation and maintenance. , 2014, Cold Spring Harbor perspectives in medicine.

[33]  Joseph E Chambers,et al.  Endoplasmic reticulum stress in malignancy. , 2014, Cancer cell.

[34]  M. Ferrari,et al.  XBP1 Promotes Triple Negative Breast Cancer By Controlling the HIF1 α Pathway , 2014, Nature.

[35]  L. Staudt,et al.  Oncogenic mechanisms in Burkitt lymphoma. , 2014, Cold Spring Harbor perspectives in medicine.

[36]  F. Brandizzi,et al.  IRE1: ER stress sensor and cell fate executor. , 2013, Trends in cell biology.

[37]  William A Weiss,et al.  Neuroblastoma and MYCN. , 2013, Cold Spring Harbor perspectives in medicine.

[38]  A. Hassell,et al.  Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development. , 2013, ACS medicinal chemistry letters.

[39]  G. Juhász,et al.  Myc-Driven Overgrowth Requires Unfolded Protein Response-Mediated Induction of Autophagy and Antioxidant Responses in Drosophila melanogaster , 2013, PLoS genetics.

[40]  C. Dang.  MYC, metabolism, cell growth, and tumorigenesis. , 2013, Cold Spring Harbor perspectives in medicine.

[41]  A. Mancuso,et al.  Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. , 2013, Genes & development.

[42]  E. White,et al.  Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids , 2013, Proceedings of the National Academy of Sciences.

[43]  Christian M. Metallo,et al.  Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells , 2013, Nature.

[44]  J. Copland,et al.  Stearoyl-CoA Desaturase 1 Is a Novel Molecular Therapeutic Target for Clear Cell Renal Cell Carcinoma , 2013, Clinical Cancer Research.

[45]  O. Sansom,et al.  MYC‐y mice: From tumour initiation to therapeutic targeting of endogenous MYC , 2013, Molecular oncology.

[46]  D. Ron,et al.  Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains , 2013, Proceedings of the National Academy of Sciences.

[47]  K. Stegmaier,et al.  Targeting MYCN in neuroblastoma by BET bromodomain inhibition. , 2013, Cancer discovery.

[48]  A. Harris,et al.  Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth , 2013, Cancer & Metabolism.

[49]  C. Koumenis,et al.  PERK-ing up autophagy during MYC-induced tumorigenesis , 2013, Autophagy.

[50]  I. Mills,et al.  ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. , 2012, The Journal of clinical investigation.

[51]  Qingbo Xu,et al.  XBP1 mRNA Splicing Triggers an Autophagic Response in Endothelial Cells through BECLIN-1 Transcriptional Activation* , 2012, The Journal of Biological Chemistry.

[52]  L. Glimcher,et al.  Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice. , 2012, Cell metabolism.

[53]  C. Croce,et al.  Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice. , 2012, Blood.

[54]  C. Harrison,et al.  Burkitt's lymphoma , 2012, The Lancet.

[55]  Chi V Dang,et al.  MYC on the Path to Cancer , 2012, Cell.

[56]  B. Wang,et al.  SCD1 Inhibition Causes Cancer Cell Death by Depleting Mono-Unsaturated Fatty Acids , 2012, PloS one.

[57]  R. Silverman,et al.  The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule , 2012, Proceedings of the National Academy of Sciences.

[58]  C. Hetz.  The unfolded protein response: controlling cell fate decisions under ER stress and beyond , 2012, Nature Reviews Molecular Cell Biology.

[59]  N. Munshi,et al.  Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma. , 2011, Blood.

[60]  E. White,et al.  Liquid chromatography-high resolution mass spectrometry analysis of fatty acid metabolism. , 2011, Analytical chemistry.

[61]  R. Young,et al.  BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc , 2011, Cell.

[62]  J. Tamburini,et al.  Dual Inhibition of PI3K and mTORC1/2 Signaling by NVP-BEZ235 as a New Therapeutic Strategy for Acute Myeloid Leukemia , 2010, Clinical Cancer Research.

[63]  Liu Yang,et al.  A Phos-Tag-Based Approach Reveals the Extent of Physiological Endoplasmic Reticulum Stress , 2010, PloS one.

[64]  C. Dang,et al.  Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model , 2010, Proceedings of the National Academy of Sciences.

[65]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[66]  Geoffrey L. Francis,et al.  Albumin and mammalian cell culture: implications for biotechnology applications , 2010, Cytotechnology.

[67]  Annette M. McGehee,et al.  XBP-1-Deficient Plasmablasts Show Normal Protein Folding but Altered Glycosylation and Lipid Synthesis1 , 2009, The Journal of Immunology.

[68]  J. Weissman,et al.  Regulated Ire1-dependent decay of messenger RNAs in mammalian cells , 2009, The Journal of cell biology.

[69]  R. Clarke,et al.  The role of X-box binding protein-1 in tumorigenicity. , 2009, Drug news & perspectives.

[70]  B. Hoffman,et al.  Apoptotic signaling by c-MYC , 2008, Oncogene.

[71]  Davide Ruggero,et al.  Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency , 2008, Nature.

[72]  Martin-Leo Hansmann,et al.  Origin and pathogenesis of nodular lymphocyte–predominant Hodgkin lymphoma as revealed by global gene expression analysis , 2008, The Journal of experimental medicine.

[73]  L. Glimcher,et al.  Regulation of Hepatic Lipogenesis by the Transcription Factor XBP1 , 2008, Science.

[74]  M. Hogarty,et al.  N-myc augments death and attenuates protective effects of Bcl-2 in trophically stressed neuroblastoma cells , 2008, Oncogene.

[75]  Thomas C. Chen,et al.  The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. , 2007, Cancer research.

[76]  G. Morgan,et al.  Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. , 2007, Blood.

[77]  Nathan H. Lents,et al.  XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. , 2007, Molecular cell.

[78]  P. Walter,et al.  Signal integration in the endoplasmic reticulum unfolded protein response , 2007, Nature Reviews Molecular Cell Biology.

[79]  S. Elledge,et al.  The ubiquitin-specific protease USP28 is required for MYC stability , 2007, Nature Cell Biology.

[80]  Bianca Sperl,et al.  Selective Inhibition of c‐Myc/Max Dimerization by a Pyrazolo[1,5‐a]pyrimidine , 2007, ChemMedChem.

[81]  Adam A. Margolin,et al.  Reverse engineering of regulatory networks in human B cells , 2005, Nature Genetics.

[82]  F. Moatamed,et al.  In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. , 2004, Blood.

[83]  Gerard Lozanski,et al.  Adult Burkitt leukemia and lymphoma. , 2004, Blood.

[84]  M. Bjornsti,et al.  The tor pathway: a target for cancer therapy , 2004, Nature Reviews Cancer.

[85]  L. Glimcher,et al.  XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response , 2003, Molecular and Cellular Biology.

[86]  Kathryn A. O’Donnell,et al.  An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets , 2003, Genome Biology.

[87]  Neal N. Iwakoshi,et al.  Plasma cell differentiation requires the transcription factor XBP-1 , 2001, Nature.

[88]  Chen-feng Qi,et al.  Burkitt Lymphoma in the Mouse , 2000, The Journal of experimental medicine.

[89]  F. Alt,et al.  N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation. , 2000, Genes & development.

[90]  F. Urano,et al.  Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. , 2000, Science.

[91]  Robert A. Weinberg,et al.  Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes , 1983, Nature.

[92]  J. Bishop,et al.  Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29 , 1978, Journal of virology.

[93]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[94]  Robert E. Cooke,et al.  Perspectives in Medicine , 1949, The Yale Journal of Biology and Medicine.

[95]  J. Ochocki,et al.  HIF-2α dependent lipid storage promotes endoplasmic reticulum homeostasis in clear cell renal cell carcinoma , 2015 .

[96]  Mauro Ferrari,et al.  XBP 1 Promotes Triple Negative Breast Cancer By Controlling the HIF 1 α Pathway , 2014 .

[97]  Erin Murphy,et al.  SCD 1 Inhibition Causes Cancer Cell Death by Depleting MonoUnsaturated Fatty Acids , 2012 .

[98]  J. Ntambi,et al.  Stearoyl CoA desaturase 1: role in cellular inflammation and stress. , 2011, Advances in nutrition.

[99]  F. Urano,et al.  Measuring ER stress and the unfolded protein response using mammalian tissue culture system. , 2011, Methods in enzymology.

[100]  P. Damas,et al.  [Inflammation and stress]. , 1999, Revue medicale de Liege.