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
View: Text | PDF
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

×

Figure 5

B-I09 treatment results in phenotypes dependent on SCD1 loss in P493 cells.

Options: View larger image (or click on image) Download as PowerPoint
B-I09 treatment results in phenotypes dependent on SCD1 loss in P493 cel...
(A) Heatmap shows relative expression of lipid metabolism genes in P493 cells with different c-Myc levels upon 10 μM B-I09 treatment for 48 hours (n = 3). Expression signals are depicted using pseudocoloring, in which expression for each gene is shown as high (red) or low (blue). (B) U-13C-glucose tracing and fatty acid labeling in P493 High Myc and No Myc cells with 10 μM B-I09 treatment for 24 hours (n = 3). Labeled/total ratios were calculated for palmitate (C16:0), stearate (C:18:0), and oleate (C18:1). (C) Immunoblot analysis for P493 cells treated with DMSO or B-I09 for 48 hours. (D) Mean enrichment of C18:1/C18:0 was calculated in P493 High Myc cells from data in B (n = 3, 2-tailed Student’s t test). (E) ChIP-qPCR assay performed using anti-XBP1s antibody to detect enriched gene-promoter fragments in 3 conditions: control (Ct); tunicamycin (5 μg/ml) treatment for 6 hours (Tm); and tunicamycin+B-I09 (10 μM) treatment for 6 hours (Tm+B-I09). IgG was used as mock ChIP control. ERdj4 serves as a positive control for XBP1s binding. Values represent relative increase of real-time PCR signals compared with the signal of IgG ChIP under control conditions. Three technical triplicates are presented. (F) Cell growth of P493 High Myc cells treated with 10 μM B-I09 and rescued with BSA control or OA (n = 3). (G) Relative viability of P493 High Myc cells treated with 10 μM B-I09 and rescued with BSA control, OA, or POA for 48 hours. 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 < 0.001.