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

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 7

IRAK4 inhibition potentiates the cytotoxic effect of chemotherapy in vivo.

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IRAK4 inhibition potentiates the cytotoxic effect of chemotherapy in viv...
(A and B) Combination indices between AS2444697 (A) or PF06650833 (B) and chemotherapeutic agents 5-FU, oxaliplatin, and SN-38 in 3 different CRC lines calculated using CompuSyn software. Cells were cultured in 6 fixed-ratio concentrations in triplicate over 72 hours and viability assayed by Alamar Blue. The concentrations (in μM) of IRAK4 inhibitor and each chemotherapeutic agent (5-FU or oxaliplatin or SN-38) were 8 and 50, 4 and 25, 2 and 12.5, 1 and 6.25, 0.5 and 3.125, and 0.25 and 1.56. Experiments were done 3 times in triplicate, and 1 set of data is presented as mean ± SEM. (C) Final weight and picture of DLD-1 tumors harvested simultaneously when vehicle-treated mice reached maximum volume of approximately 2000 mm3. Data represent mean ± SEM (Tukey’s multiple-comparisons test, *P < 0.05, ***P < 0.001). (D and E) Quantification of cleaved caspase-3+ area per ×200 field (D) and dual CK+ and Ki-67+ cells per ×400 field (E) of DLD-1 tumors treated as indicated. Ten random pictures were taken from each 10 tumors per arm, and data represent mean ± SEM (Tukey’s multiple-comparisons test, **P < 0.01, ***P < 0.001). (F) Kaplan-Meier survival of mice bearing DLD-1 tumors treated as indicated when tumors reached 100 mm3 and until tumor volume exceeded 2000 mm3 or whenever humane endpoints were reached (n = 10 per group, log-rank test). (G) Final weight and picture of KM12 tumors harvested simultaneously when vehicle-treated mice reached maximum volume of approximately 2000 mm3. Data represent mean ± SEM (Tukey’s multiple-comparisons test, *P < 0.05, ***P < 0.001). (H and I) Quantification of cleaved caspase-3+ area per ×200 field (H) and dual CK+ and Ki-67+ cells per ×400 field (I) of KM12 tumors treated as indicated. Ten random pictures were taken from each 10 tumors per arm, and data represent mean ± SEM (Tukey’s multiple-comparisons test, *P < 0.05, **P < 0.01, ***P < 0.001). (J) Kaplan-Meier survival of mice bearing KM12 tumors treated as indicated when tumors reached 100 mm3 and until tumor volume exceeded 2000 mm3 or whenever humane endpoints were reached (n = 10 per group, log-rank test).