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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 9

Schematics depicting a proposed model in which DNA damage incurred by chemotherapy triggers a TLR9–IRAK4–NF-κB circuitry to sustain CRC cell survival.

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Schematics depicting a proposed model in which DNA damage incurred by ch...
At basal state, IRAK4 and NF-κB are activated through mechanisms that remain to be determined, but likely through upstream TIR family members including TLR9. Upon exposure to chemotherapy, damaged DNA may activate NF-κB through ATM and engage the preexisting pool of TLR9, which in turn activates IRAK4 and NF-κB, resulting in survival and further upregulation of TLR9. This chain of events results in enhanced survival, which enables CRC cells to evade chemotherapy-induced apoptosis.

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