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 7

N-Myc activates the IRE1α/XBP1 pathway, rendering cells vulnerable to XBP1s loss.

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N-Myc activates the IRE1α/XBP1 pathway, rendering cells vulnerable to XB...
(A–D) SHEP N-MycER cells were treated with 4-OHT (200 nM) to activate N-Myc nuclear translocation (A). XBP1s/XBP1t ratios examined with qRT-PCR (B) (n = 3). XBP1 splicing analyzed by RT-PCR (C) and XBP1s protein accumulation determined by immunoblots (D). (E) SHEP cells cultured in vehicle (control) or 4-OHT containing medium for 48 hours before treatment with DMSO or B-I09. WST-1 assay was used to examine cell growth. Relative absorbance was determined by normalizing to absorbance at time 0 hours (n = 6). IC50 was then determined (n = 3, 2-tailed Student’s t test). (F) Representative contour plots of control and 4-OHT SHEP cells treated with 30 μM B-I09 for 96 hours. (G) SHEP cells pretreated with CHX (0.5 μg/ml) for 2 hours and then cultured with DMSO or 30 μM B-I09 for 72 hours. Relative viability was determined by normalizing to viability upon DMSO treatment or DMSO+CHX treatment, respectively. (H) Immunoblot for control and 4-OHT SHEP cells with B-I09 treatment for 72 hours. (I) Control or N-Myc SHEP cells treated with DMSO or B-I09 and rescued with BSA or OA for 72 hours. Viability was examined and relative viability was determined by normalizing to viability upon DMSO treatment. For viability assays, results are representative of 3 independent experiments. P values were determined by 2-way ANOVA with Bonferroni’s correction, if not specified elsewhere. *P < 0.05, ***P < 0.001 (B, E and B, E, and G); ***P < 0.001, comparison of B-I09 and DMSO treatment; ###P < 0.001, comparison of B-I09+BSA or B-I09+OA and B-I09 treatment (I).