IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers
Hong Xie, … , Chih-Chi Andrew Hu, M. Celeste Simon
Hong Xie, … , Chih-Chi Andrew Hu, M. Celeste Simon
Published April 2, 2018; First published January 30, 2018
Citation Information: J Clin Invest. 2018;128(4):1300-1316. https://doi.org/10.1172/JCI95864.
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Categories: Research Article Oncology Therapeutics

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

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.

Authors

Hong Xie, Chih-Hang Anthony Tang, Jun H. Song, Anthony Mancuso, Juan R. Del Valle, Jin Cao, Yan Xiang, Chi V. Dang, Roy Lan, Danielle J. Sanchez, Brian Keith, Chih-Chi Andrew Hu, M. Celeste Simon

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Figure 1

ER stress and IRE1α/XBP1 signaling are enhanced in human and mouse BL.

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ER stress and IRE1α/XBP1 signaling are enhanced in human and mouse BL. (...
(A) Schematic model of the IRE1α/XBP1 pathway. (B) log2 median-centered intensity of HSPA5 in human BL (n = 17) and CB (n = 5, 2-tailed Student’s t test). Microarray data were obtained from the Oncomine database. Whiskers denote the minimal to maximal values. (C) Correlation of MYC and HSPA5 in samples from B. R2 and P values were determined by a 2-tailed Pearson correlation test. (D) In 2 independent cohorts of BL patients and CB controls, heatmap shows the relative expression of genes directly regulated by XBP1s. Data were extracted from the Oncomine database. Expression signals are depicted using pseudocoloring, in which expression for each gene is shown as high (red) or low (blue). (E) qRT-PCR analysis of Xbp1s/Xbp1t ratios in mixed B lymphocytes isolated from 2 WT mouse spleens and tumor cells from superficial and mesenteric lymphomas in 7 Eλ/MYC mice. Actb was utilized as the endogenous control gene, and relative mRNA expression was determined by normalizing to expression in WT B lymphocytes. Three technical triplicates were used in each sample.