Journal article
LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation
Cells (Basel, Switzerland), Vol.13(7), 565
03/23/2024
DOI: 10.3390/cells13070565
PMCID: PMC11011703
PMID: 38607004
Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson's disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer. Despite this observation, the underlying mechanisms linking LRRK2 G2019S to colon cancer remain elusive. In this study, employing a colitis-associated cancer (CAC) model and LRRK2 G2019S knock-in (KI) mouse model, we demonstrate that LRRK2 G2019S promotes the pathogenesis of colon cancer, characterized by increased tumor number and size in KI mice. Furthermore, LRRK2 G2019S enhances intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, KI mice exhibit heightened susceptibility to DSS-induced colitis, with inhibition of LRRK2 kinase activity ameliorating colitis severity and CAC progression. Our investigation also reveals that LRRK2 G2019S promotes inflammasome activation and exacerbates gut epithelium necrosis in the colitis model. Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.
Details
- Title: Subtitle
- LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation
- Creators
- Yuhang Wang - University of IowaJoyce Z Gao - University of IowaTaylor Sakaguchi - University of IowaThorsten Maretzky - University of IowaPrajwal Gurung - University of IowaNandakumar S Narayanan - University of IowaSarah Short - University of IowaYiqin Xiong - University of IowaZizhen Kang - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cells (Basel, Switzerland), Vol.13(7), 565
- DOI
- 10.3390/cells13070565
- PMID
- 38607004
- PMCID
- PMC11011703
- eISSN
- 2073-4409
- Grant note
- R21AG076895 / NIH HHS R01 NS104164 / NIH HHS
- Language
- English
- Date published
- 03/23/2024
- Academic Unit
- Neurology; Infectious Diseases; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Iowa Neuroscience Institute; Internal Medicine
- Record Identifier
- 9984583618902771
Metrics
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