Hepatic IRE1α-XBP1 branch of the UPR is selectively activated by chemotherapy. (A) Schematic illustration of the experimental design. 8-wk-old C57BL/6 male mice were treated with Vehicle (n = 5), a single dose of DOX (10 mg per kg body weight, i.p., n = 5), or Cis (10 mg per kg body weight, i.p., n = 5) for 1 day before liver samples were collected for bulk RNA-seq. (B) Principal component analysis of transcriptomic data obtained by bulk RNA-seq of liver tissue from mice treated with Vehicle, DOX, or Cis for 1 day. (C) Heatmap visualization of the expression patterns of differentially expressed genes (DEGs) following chemotherapeutic drug administration. The cutoff values are |Log2(Foldchange)| > 0.5, and P value < 0.05. For each group, the expression value is shown for five mice. (D) The top 10 enriched HALLMARK pathways by GSEA, which are differentially regulated in livers from Vehicle- and DOX-treated mice. HALLMARK pathways are defined using FPKM (fragments per kilobase million) values of all the detected genes in livers from DOX-treated mice and ranked according to NES. (E) GSEA plot indicating the enrichment (NES = 2.43 and FDR q-value < 0.001) of “IRE1-mediated unfolded protein response” gene signature in DOX-treated mice. The solid bars represent individual genes in this gene set. (F and G) 8-wk-old C57BL/6 male mice were treated with a single dose of (F) DOX (10 mg per kg body weight, i.p.) or (G) Cis (10 mg per kg body weight, i.p.). Liver samples were collected at indicated time (0, 1, 3, and 7 days) after injection. Western blot analysis showing the levels of the indicated proteins in liver lysates from the indicated mice. Each sample represents an individual animal. Tubulin was used as a loading control. (H–J)Xbp1 mRNA splicing (H), mRNA levels of the indicated XBP1s target genes (I), and ER stress markers (J) in livers from mice treated with DOX (10 mg per kg body weight, i.p.), Cis (10 mg per kg body weight, i.p.), or PTX (10 mg per kg body weight, i.p.) for 0 (n = 4), 1 (n = 6), 3 (n = 6), and 7 days (n = 6). Data are representative of two independent experiments and presented as mean ± SEM. *P < 0.05, **P < 0.01, or ***P < 0.001 by one-way ANOVA (H–J). Source data are available for this figure: SourceData F1.
Figure 1.

Hepatic IRE1α-XBP1 branch of the UPR is selectively activated by chemotherapy. (A) Schematic illustration of the experimental design. 8-wk-old C57BL/6 male mice were treated with Vehicle (n = 5), a single dose of DOX (10 mg per kg body weight, i.p., n = 5), or Cis (10 mg per kg body weight, i.p., n = 5) for 1 day before liver samples were collected for bulk RNA-seq. (B) Principal component analysis of transcriptomic data obtained by bulk RNA-seq of liver tissue from mice treated with Vehicle, DOX, or Cis for 1 day. (C) Heatmap visualization of the expression patterns of differentially expressed genes (DEGs) following chemotherapeutic drug administration. The cutoff values are |Log2(Foldchange)| > 0.5, and P value < 0.05. For each group, the expression value is shown for five mice. (D) The top 10 enriched HALLMARK pathways by GSEA, which are differentially regulated in livers from Vehicle- and DOX-treated mice. HALLMARK pathways are defined using FPKM (fragments per kilobase million) values of all the detected genes in livers from DOX-treated mice and ranked according to NES. (E) GSEA plot indicating the enrichment (NES = 2.43 and FDR q-value < 0.001) of “IRE1-mediated unfolded protein response” gene signature in DOX-treated mice. The solid bars represent individual genes in this gene set. (F and G) 8-wk-old C57BL/6 male mice were treated with a single dose of (F) DOX (10 mg per kg body weight, i.p.) or (G) Cis (10 mg per kg body weight, i.p.). Liver samples were collected at indicated time (0, 1, 3, and 7 days) after injection. Western blot analysis showing the levels of the indicated proteins in liver lysates from the indicated mice. Each sample represents an individual animal. Tubulin was used as a loading control. (H–J)Xbp1 mRNA splicing (H), mRNA levels of the indicated XBP1s target genes (I), and ER stress markers (J) in livers from mice treated with DOX (10 mg per kg body weight, i.p.), Cis (10 mg per kg body weight, i.p.), or PTX (10 mg per kg body weight, i.p.) for 0 (n = 4), 1 (n = 6), 3 (n = 6), and 7 days (n = 6). Data are representative of two independent experiments and presented as mean ± SEM. *P < 0.05, **P < 0.01, or ***P < 0.001 by one-way ANOVA (H–J). Source data are available for this figure: SourceData F1.

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