TY - JOUR
T1 - Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer
AU - Karki, Rajendra
AU - Sharma, Bhesh Raj
AU - Lee, Ein
AU - Banoth, Balaji
AU - Malireddi, R. K.Subbarao
AU - Samir, Parimal
AU - Tuladhar, Shraddha
AU - Mummareddy, Harisankeerth
AU - Burton, Amanda R.
AU - Vogel, Peter
AU - Kanneganti, Thirumala Devi
N1 - Funding Information:
We thank members of the Kanneganti lab for their comments and suggestions. Several images were acquired at the St. Jude Cell & Tissue Imaging Center, which is supported by St. Jude Children’s Research Hospital and National Cancer Institute grant P30 CA021765-35. We also thank Rebecca Tweedell for scientific editing and writing support. Work from our laboratory is supported by the US NIH (grants AI101935, AI124346, AR056296, and CA163507 to TDK) and the American Lebanese Syrian Associated Charities (to TDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/6/18
Y1 - 2020/6/18
N2 - Interferon regulatory factor 1 (IRF1) regulates diverse biological functions, including modulation of cellular responses involved in tumorigenesis. Genetic mutations and altered IRF1 function are associated with several cancers. Although the function of IRF1 in the immunobiology of cancer is emerging, IRF1-specific mechanisms regulating tumorigenesis and tissue homeostasis in vivo are not clear. Here, we found that mice lacking IRF1 were hypersusceptible to colorectal tumorigenesis. IRF1 functions in both the myeloid and epithelial compartments to confer protection against AOM/DSS-induced colorectal tumorigenesis. We further found that IRF1 also prevents tumorigenesis in a spontaneous mouse model of colorectal cancer. The attenuated cell death in the colons of Irf1–/–mice was due to defective pyroptosis, apoptosis, and necroptosis (PANoptosis). IRF1 does not regulate inflammation and the inflammasome in the colon. Overall, our study identified IRF1 as an upstream regulator of PANoptosis to induce cell death during colitis-associated tumorigenesis.
AB - Interferon regulatory factor 1 (IRF1) regulates diverse biological functions, including modulation of cellular responses involved in tumorigenesis. Genetic mutations and altered IRF1 function are associated with several cancers. Although the function of IRF1 in the immunobiology of cancer is emerging, IRF1-specific mechanisms regulating tumorigenesis and tissue homeostasis in vivo are not clear. Here, we found that mice lacking IRF1 were hypersusceptible to colorectal tumorigenesis. IRF1 functions in both the myeloid and epithelial compartments to confer protection against AOM/DSS-induced colorectal tumorigenesis. We further found that IRF1 also prevents tumorigenesis in a spontaneous mouse model of colorectal cancer. The attenuated cell death in the colons of Irf1–/–mice was due to defective pyroptosis, apoptosis, and necroptosis (PANoptosis). IRF1 does not regulate inflammation and the inflammasome in the colon. Overall, our study identified IRF1 as an upstream regulator of PANoptosis to induce cell death during colitis-associated tumorigenesis.
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U2 - 10.1172/jci.insight.136720
DO - 10.1172/jci.insight.136720
M3 - Article
C2 - 32554929
AN - SCOPUS:85086693659
SN - 2379-3708
VL - 5
JO - JCI insight
JF - JCI insight
IS - 12
M1 - 136720
ER -