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IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer
Qiong Li, … , Ryan C. Fields, Kian-Huat Lim
Qiong Li, … , Ryan C. Fields, Kian-Huat Lim
Published September 17, 2019
Citation Information: JCI Insight. 2019;4(19):e130867. https://doi.org/10.1172/jci.insight.130867.
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Research Article Oncology Therapeutics

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

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Abstract

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor–associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.

Authors

Qiong Li, Yali Chen, Daoxiang Zhang, Julie Grossman, Lin Li, Namrata Khurana, Hongmei Jiang, Patrick M. Grierson, John Herndon, David G. DeNardo, Grant A. Challen, Jingxia Liu, Marianna B. Ruzinova, Ryan C. Fields, Kian-Huat Lim

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Figure 6

Chemotherapy induces autologous TLR9–IRAK4–NF-κB circuitry.

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Chemotherapy induces autologous TLR9–IRAK4–NF-κB circuitry.
(A) Lucifera...
(A) Luciferase reporter assay showing the effect of chemotherapy on NF-κB activity in 2 different CRC lines. Data represent 1 of 3 sets of experiments each done in triplicate and presented as mean ± SEM (ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001). (B) Quantitative PCR showing changes in expression of the indicated genes in 3 CRC lines following exposure to chemotherapy (5-FU and oxaliplatin, both 10 μM) overnight. Data represent 1 of 2 sets of experiments each done in biological duplicates and technical triplicates and presented as mean ± SEM. (C) Western blots confirming increased protein expression of TLR9 following overnight treatment with the indicated chemotherapeutic agent (all at 10 μM) in HCT-116 (left panel) and 3 different CRC lines (right panel). (D) Representative (×400) confocal images and quantification (mean ± SEM) of proximal ligation assay (PLA) puncta (red) formed between TLR9 (CST #D9M9H) and p-IRAK4 (ABNOVA #A8A8, 1:500) in 3 colon lines treated with vehicle or chemotherapy (5-FU and oxaliplatin, both 10 μM) overnight (2-tailed t test, **P < 0.01). (E) Western blots showing the effect of TLR9 knockdown on chemotherapy-induced PARP cleavage in HCT-116 cells. (F) Luciferase reporter assay showing the effect of TLR9 knockdown on chemotherapy-induced NF-κB activity in HCT-116 cells (ANOVA, *P < 0.05, **P < 0.01). (G) Western blots showing suppressive effects of IRAK4 and IKK inhibitors on chemotherapy-induced TLR9 expression and apoptosis. (H) Quantitative PCR showing suppressive effect of IRAK4i (PF06650833, 4 μM overnight) on chemotherapy-induced TLR9 expression. Data represent 1 of 2 sets of experiments each done in biological duplicates and technical triplicates and presented as mean ± SEM (Tukey’s multiple-comparisons test, *P < 0.05, **P < 0.01, ***P < 0.001).

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