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

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 2

c-Myc affects ER stress and the IRE1α/XBP1 pathway through multiple molecular mechanisms.

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c-Myc affects ER stress and the IRE1α/XBP1 pathway through multiple mole...
(A) P493 No Myc, Low Myc, and High Myc cells analyzed by flow cytometry to determine cell size using forward scatter (results are representative of >3 independent experiments). (B) Protein content of 1 million P493 No Myc, Low Myc, and High Myc cells (n = 6, 2-way ANOVA test with Bonferroni’s correction). (C) qRT-PCR analysis of ERN1, HSPA5, XBP1t, XBP1s, and XBP1s/XBP1t ratios in P493 cells with different levels of c-Myc (n = 3, 2-way ANOVA test with Bonferroni’s correction). (D) RT-PCR analysis of XBP1 splicing in P493 cells. (E) Immunoblot analysis for IRE1α phosphorylation (phos-tag SDS-PAGE), BiP, and XBP1s in P493 cells. SE, short time exposure; LE, long time exposure. (F) In P493 cells, c-Myc was suppressed with tetracycline (0.1 μg/ml) for 24 hours, which was then withdrawn to reexpress c-Myc. At indicated times, mRNA was collected for qRT-PCR analysis. Three technical triplicates were used in each sample, and results are representative of more than 3 independent experiments. (G) Corresponding RT-PCR and immunoblot analysis of data in F. (H) Comparison of ER structures using transmission electron microscopy in P493 cells with or without c-Myc overexpression. Scale bars: 500 nm. (I) Schematic model of c-Myc regulating ER stress and the IRE1α/XBP1 pathway. For qRT-PCR, ACTB was utilized as the endogenous control gene. *P < 0.05; **P < 0.01; ***P < 0.001.