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

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; Mari Mino-Kenudson; Shadmehr Demehri

doi:10.1038/s41467-024-48441-8

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

Nat Commun. 2024 May 30;15(1):4099. doi: 10.1038/s41467-024-48441-8.

Authors

Jong Ho Park^{1

2

3}, Mahsa Mortaja^{1

2}, Heehwa G Son^{1

2}, Xutu Zhao^{1

2}, Lauren M Sloat^{1

2}, Marjan Azin^{1

2}, Jun Wang², Michael R Collier⁴, Krishna S Tummala^{5

6

7

8

9}, Anna Mandinova², Nabeel Bardeesy^{5

6

7

8}, Yevgeniy R Semenov^{4

10}, Mari Mino-Kenudson¹¹, Shadmehr Demehri^{12

13

14}

Affiliations

¹ Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Department of Anatomy, School of Medicine, Keimyung University, Daegu, South Korea.
⁴ Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁸ Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
⁹ Quantitative Biosciences, Merck Research Laboratories, Boston, MA, USA.
¹⁰ Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, USA.
¹¹ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹² Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. sdemehri1@mgh.harvard.edu.
¹³ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. sdemehri1@mgh.harvard.edu.
¹⁴ Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. sdemehri1@mgh.harvard.edu.

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.

MeSH terms

Animals
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
Inflammation / metabolism
Inflammation / prevention & control
Interferon Regulatory Factor-3* / metabolism
Interleukin-33* / drug effects
Interleukin-33* / metabolism
Male
Mevalonic Acid / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism
Pancreatic Neoplasms* / prevention & control
Pancreatitis, Chronic / metabolism
Pancreatitis, Chronic / prevention & control
Protein Serine-Threonine Kinases* / metabolism
Quinolines* / pharmacology
Quinolines* / therapeutic use
Signal Transduction* / drug effects
Toll-Like Receptor 3 / metabolism
Toll-Like Receptor 4 / metabolism

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors
IL33 protein, human
Il33 protein, mouse
Interferon Regulatory Factor-3
Interleukin-33
Irf3 protein, mouse
Mevalonic Acid
pitavastatin
Protein Serine-Threonine Kinases
Quinolines
TBK1 protein, human
Tbk1 protein, mouse
Toll-Like Receptor 3
Toll-Like Receptor 4

Abstract

MeSH terms

Substances

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