IRE1α 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...

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Published in:	The Journal of clinical investigation Vol. 128; no. 4; pp. 1300 - 1316
Main Authors:	Xie, Hong, Tang, Chih-Hang Anthony, Song, Jun H, Mancuso, Anthony, Del Valle, Juan R, Cao, Jin, Xiang, Yan, Dang, Chi V, Lan, Roy, Sanchez, Danielle J, Keith, Brian, Hu, Chih-Chi Andrew, Simon, M Celeste
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 02-04-2018
Subjects:	Activating transcription factor 1 Apoptosis Biomedical research Breast cancer Burkitt's lymphoma c-Myc protein Cancer therapies Chemotherapy Cytotoxicity Desaturase Drug development Endoplasmic reticulum Enzymes Fatty acids Homeostasis Inositol Kinases Lipids Lymphoma Metabolism Molecular modelling Myc protein Neuroblastoma Physiology Proteins Ribonuclease Sensors Therapeutic applications Transcription factors Tumorigenesis Oncology Cell stress Drug therapy Therapeutics Cancer
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Abstract	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 1α (IRE1α)/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 IRE1α/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 IRE1α RNase activity suppression in vivo. Furthermore, IRE1α inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc-overexpressing Burkitt's lymphoma, suggesting that inhibiting the IRE1α/XBP1 pathway is a useful general strategy for treatment of Myc-driven cancers.
AbstractList	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 1a (IRE1a)/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 IRE1a/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 IRE1a RNase activity suppression in vivo. Furthermore, IRE1a inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc-overexpressing Burkitt's lymphoma, suggesting that inhibiting the IRE1a/XBP1 pathway is a useful general strategy for treatment of Myc-driven 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 1α (IRE1α)/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 IRE1α/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 IRE1α RNase activity suppression in vivo. Furthermore, IRE1α inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc-overexpressing Burkitt's lymphoma, suggesting that inhibiting the IRE1α/XBP1 pathway is a useful general strategy for treatment of Myc-driven cancers.
Author	Del Valle, Juan R Tang, Chih-Hang Anthony Xiang, Yan Hu, Chih-Chi Andrew Lan, Roy Keith, Brian Sanchez, Danielle J Dang, Chi V Song, Jun H Xie, Hong Cao, Jin Mancuso, Anthony Simon, M Celeste
AuthorAffiliation	3 The Wistar Institute, Philadelphia, Pennsylvania, USA 1 Abramson Family Cancer Research Institute and 4 Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 2 Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 8 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA 7 Lester and Sue Smith Breast Center, and 6 Department of Molecular and Cellular Biology 5 Department of Chemistry, University of South Florida, Tampa, Florida, USA
AuthorAffiliation_xml	– name: 4 Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA – name: 7 Lester and Sue Smith Breast Center, and – name: 1 Abramson Family Cancer Research Institute and – name: 6 Department of Molecular and Cellular Biology – name: 8 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA – name: 3 The Wistar Institute, Philadelphia, Pennsylvania, USA – name: 2 Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA – name: 5 Department of Chemistry, University of South Florida, Tampa, Florida, USA
Author_xml	– sequence: 1 givenname: Hong surname: Xie fullname: Xie, Hong organization: Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 2 givenname: Chih-Hang Anthony surname: Tang fullname: Tang, Chih-Hang Anthony organization: The Wistar Institute, Philadelphia, Pennsylvania, USA – sequence: 3 givenname: Jun H surname: Song fullname: Song, Jun H organization: Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 4 givenname: Anthony surname: Mancuso fullname: Mancuso, Anthony organization: Abramson Family Cancer Research Institute and – sequence: 5 givenname: Juan R surname: Del Valle fullname: Del Valle, Juan R organization: Department of Chemistry, University of South Florida, Tampa, Florida, USA – sequence: 6 givenname: Jin surname: Cao fullname: Cao, Jin organization: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA – sequence: 7 givenname: Yan surname: Xiang fullname: Xiang, Yan organization: Abramson Family Cancer Research Institute and – sequence: 8 givenname: Chi V surname: Dang fullname: Dang, Chi V organization: Abramson Family Cancer Research Institute and – sequence: 9 givenname: Roy surname: Lan fullname: Lan, Roy organization: Abramson Family Cancer Research Institute and – sequence: 10 givenname: Danielle J surname: Sanchez fullname: Sanchez, Danielle J organization: Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 11 givenname: Brian surname: Keith fullname: Keith, Brian organization: Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA – sequence: 12 givenname: Chih-Chi Andrew surname: Hu fullname: Hu, Chih-Chi Andrew organization: The Wistar Institute, Philadelphia, Pennsylvania, USA – sequence: 13 givenname: M Celeste surname: Simon fullname: Simon, M Celeste organization: Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/29381485$$D View this record in MEDLINE/PubMed
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Copyright	Copyright American Society for Clinical Investigation Apr 2018 Copyright © 2018, American Society for Clinical Investigation 2018 American Society for Clinical Investigation
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Snippet	Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting...
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SubjectTerms	Activating transcription factor 1 Apoptosis Biomedical research Breast cancer Burkitt's lymphoma c-Myc protein Cancer therapies Chemotherapy Cytotoxicity Desaturase Drug development Endoplasmic reticulum Enzymes Fatty acids Homeostasis Inositol Kinases Lipids Lymphoma Metabolism Molecular modelling Myc protein Neuroblastoma Physiology Proteins Ribonuclease Sensors Therapeutic applications Transcription factors Tumorigenesis
Title	IRE1α RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers
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