IRE1α RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers

• 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
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI95864

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.