LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation
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 indica...
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MDPI AG
2024-03-01
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| Online Access: | https://www.mdpi.com/2073-4409/13/7/565 |
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| author | Yuhang Wang Joyce Z. Gao Taylor Sakaguchi Thorsten Maretzky Prajwal Gurung Nandakumar S. Narayanan Sarah Short Yiqin Xiong Zizhen Kang |
| author_facet | Yuhang Wang Joyce Z. Gao Taylor Sakaguchi Thorsten Maretzky Prajwal Gurung Nandakumar S. Narayanan Sarah Short Yiqin Xiong Zizhen Kang |
| author_sort | Yuhang Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T10:47:38Z |
| format | Article |
| id | doaj.art-472c130cec2241ce8e3466d3b27577cb |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-04-24T10:47:38Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-472c130cec2241ce8e3466d3b27577cb2024-04-12T13:16:24ZengMDPI AGCells2073-44092024-03-0113756510.3390/cells13070565LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut InflammationYuhang Wang0Joyce Z. Gao1Taylor Sakaguchi2Thorsten Maretzky3Prajwal Gurung4Nandakumar S. Narayanan5Sarah Short6Yiqin Xiong7Zizhen Kang8Department of Pathology, University of Iowa, Iowa City, IA 52242, USADepartment of Pathology, University of Iowa, Iowa City, IA 52242, USADepartment of Pathology, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, University of Iowa, Iowa City, IA 52242, USAIowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Pathology, University of Iowa, Iowa City, IA 52242, USADepartment of Pathology, University of Iowa, Iowa City, IA 52242, USALeucine-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.https://www.mdpi.com/2073-4409/13/7/565LRRK2 G2019Scolitiscolon cancerinflammation |
| spellingShingle | Yuhang Wang Joyce Z. Gao Taylor Sakaguchi Thorsten Maretzky Prajwal Gurung Nandakumar S. Narayanan Sarah Short Yiqin Xiong Zizhen Kang LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation Cells LRRK2 G2019S colitis colon cancer inflammation |
| title | LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation |
| title_full | LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation |
| title_fullStr | LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation |
| title_full_unstemmed | LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation |
| title_short | LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation |
| title_sort | lrrk2 g2019s promotes colon cancer potentially via lrrk2 gsdmd axis mediated gut inflammation |
| topic | LRRK2 G2019S colitis colon cancer inflammation |
| url | https://www.mdpi.com/2073-4409/13/7/565 |
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