TY - JOUR
T1 - IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer
AU - Li, Qiong
AU - Chen, Yali
AU - Zhang, Daoxiang
AU - Grossman, Julie
AU - Li, Lin
AU - Khurana, Namrata
AU - Jiang, Hongmei
AU - Grierson, Patrick M.
AU - Herndon, John
AU - DeNardo, David G.
AU - Challen, Grant A.
AU - Liu, Jingxia
AU - Ruzinova, Marianna B.
AU - Fields, Ryan C.
AU - Lim, Kian Huat
N1 - Funding Information:
This study was supported by NIH grant R21 CA223112 (to KHL and MBR), the BJHF-ICTS Clinical and Translational Research Program (to KHL), Concern Foundation Conquer Cancer Award 388329 (to KHL), the SIP Award funded by the Siteman Cancer Center and the Foundation for BJH (to KHL and MBR), Surgical Oncology NCI T32 training grant (to JG), and NIH CTSA Grant UL1 TR000448 (to KHL). QL is supported by the National Natural Science Foundation of China (grant 81401735). We acknowledge the WUSTL Digestive Diseases Research Cores Center (grant P30 DK052574) for providing technical support.
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019
Y1 - 2019
N2 - 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 feedforward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phosphoIRAK4 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.
AB - 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 feedforward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phosphoIRAK4 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.
UR - http://www.scopus.com/inward/record.url?scp=85072985165&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.130867
DO - 10.1172/jci.insight.130867
M3 - Article
C2 - 31527315
AN - SCOPUS:85072985165
SN - 2379-3708
VL - 4
JO - JCI insight
JF - JCI insight
IS - 19
M1 - e130867
ER -