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Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression

Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by the environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK...

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Autores principales: Park, Jong Ho, Mortaja, Mahsa, Son, Heehwa, Azin, Marjan, Wang, Jun, Collier, Michael, Mandinova, Anna, Semenov, Yevgeniy, Mino-Kenudson, Mari, Demehri, Shadmehr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882616/
https://www.ncbi.nlm.nih.gov/pubmed/36711701
http://dx.doi.org/10.21203/rs.3.rs-2318750/v1
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author Park, Jong Ho
Mortaja, Mahsa
Son, Heehwa
Azin, Marjan
Wang, Jun
Collier, Michael
Mandinova, Anna
Semenov, Yevgeniy
Mino-Kenudson, Mari
Demehri, Shadmehr
author_facet Park, Jong Ho
Mortaja, Mahsa
Son, Heehwa
Azin, Marjan
Wang, Jun
Collier, Michael
Mandinova, Anna
Semenov, Yevgeniy
Mino-Kenudson, Mari
Demehri, Shadmehr
author_sort Park, Jong Ho
collection PubMed
description Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by the environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas. FDA-approved drug library screen identified pitavastatin as an effective IL-33 inhibitor by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevented chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. IRF3-IL-33 axis was highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlated with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3 signaling pathway suppresses IL-33 expression and cancer-prone chronic inflammation. Statins present a safe and effective therapeutic strategy to prevent chronic inflammation and its cancer sequela.
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spelling pubmed-98826162023-01-28 Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression Park, Jong Ho Mortaja, Mahsa Son, Heehwa Azin, Marjan Wang, Jun Collier, Michael Mandinova, Anna Semenov, Yevgeniy Mino-Kenudson, Mari Demehri, Shadmehr Res Sq Article Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by the environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas. FDA-approved drug library screen identified pitavastatin as an effective IL-33 inhibitor by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevented chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. IRF3-IL-33 axis was highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlated with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3 signaling pathway suppresses IL-33 expression and cancer-prone chronic inflammation. Statins present a safe and effective therapeutic strategy to prevent chronic inflammation and its cancer sequela. American Journal Experts 2023-01-12 /pmc/articles/PMC9882616/ /pubmed/36711701 http://dx.doi.org/10.21203/rs.3.rs-2318750/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Park, Jong Ho
Mortaja, Mahsa
Son, Heehwa
Azin, Marjan
Wang, Jun
Collier, Michael
Mandinova, Anna
Semenov, Yevgeniy
Mino-Kenudson, Mari
Demehri, Shadmehr
Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression
title Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression
title_full Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression
title_fullStr Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression
title_full_unstemmed Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression
title_short Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression
title_sort statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882616/
https://www.ncbi.nlm.nih.gov/pubmed/36711701
http://dx.doi.org/10.21203/rs.3.rs-2318750/v1
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