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 January 30, 2018
Citation Information: J Clin Invest. 2018;128(4):1300-1316. https://doi.org/10.1172/JCI95864.
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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 4

B-I09 suppresses growth and induces apoptosis in human and mouse BL cells.

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B-I09 suppresses growth and induces apoptosis in human and mouse BL cell...
(A–C) Ramos cells were treated with indicated concentrations of B-I09 for 24 hours (A), 48 hours (C), or 72 hours (B). Western blot shows the expressions of IRE1α, XBP1s, and c-Myc (A). Cell numbers were counted at indicated times (B) (n = 3). Cell viability was examined and relative cell viability was determined by normalizing to viability upon DMSO treatment (C). (D) Ramos cells pretreated with CHX (0.5 μg/ml) for 2 hours and then cultured with DMSO, 5 μM, or 10 μM B-I09 for 48 hours. Cell viability was then examined and relative cell viability determined by normalizing to viability upon DMSO treatment or DMSO+CHX treatment, respectively. (E–G) Raji, Daudi, and EB-2 BL cells treated with B-I09 for the indicated times. Cell numbers were counted (n = 3) and cell viability examined. (H) For B cells isolated from WT mouse spleens and 8498 cells from Eκ/MYC lymphoma tumor, protein expression of IRE1α, XBP1s, and c-Myc was compared and their sensitivities to different B-I09 concentrations at 48 hours examined. For all viability assays, results are representative of 3 independent experiments. P values were determined by 2-way ANOVA with Bonferroni’s correction. **P < 0.01; ***P < 0.001.