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

Author

Listed:
  • Jong Ho Park

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    Keimyung University)

  • Mahsa Mortaja

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Heehwa G. Son

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Xutu Zhao

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Lauren M. Sloat

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Marjan Azin

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Jun Wang

    (Massachusetts General Hospital and Harvard Medical School)

  • Michael R. Collier

    (Massachusetts General Hospital and Harvard Medical School)

  • Krishna S. Tummala

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital
    Harvard Medical School
    Broad Institute of Massachusetts Institute of Technology and Harvard)

  • Anna Mandinova

    (Massachusetts General Hospital and Harvard Medical School)

  • Nabeel Bardeesy

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital
    Harvard Medical School
    Broad Institute of Massachusetts Institute of Technology and Harvard)

  • Yevgeniy R. Semenov

    (Massachusetts General Hospital and Harvard Medical School
    Harvard Program in Therapeutic Science, Harvard Medical School)

  • Mari Mino-Kenudson

    (Massachusetts General Hospital and Harvard Medical School)

  • Shadmehr Demehri

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

Abstract

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 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 inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.

Suggested Citation

  • Jong Ho Park & Mahsa Mortaja & Heehwa G. Son & Xutu Zhao & Lauren M. Sloat & Marjan Azin & Jun Wang & Michael R. Collier & Krishna S. Tummala & Anna Mandinova & Nabeel Bardeesy & Yevgeniy R. Semenov &, 2024. "Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48441-8
    DOI: 10.1038/s41467-024-48441-8
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    References listed on IDEAS

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    1. Yi Sun & Or-yam Revach & Seth Anderson & Emily A. Kessler & Clara H. Wolfe & Anne Jenney & Caitlin E. Mills & Emily J. Robitschek & Thomas G. R. Davis & Sarah Kim & Amina Fu & Xiang Ma & Jia Gwee & Pa, 2023. "Targeting TBK1 to overcome resistance to cancer immunotherapy," Nature, Nature, vol. 615(7950), pages 158-167, March.
    2. Direna Alonso-Curbelo & Yu-Jui Ho & Cassandra Burdziak & Jesper L. V. Maag & John P. Morris & Rohit Chandwani & Hsuan-An Chen & Kaloyan M. Tsanov & Francisco M. Barriga & Wei Luan & Nilgun Tasdemir & , 2021. "A gene–environment-induced epigenetic program initiates tumorigenesis," Nature, Nature, vol. 590(7847), pages 642-648, February.
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