International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
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Suppression of Glioblastoma Stem Cell Potency and Tumor Growth via LRRK2 Inhibition

  • Saewhan Park (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Kyung-Hee Kim (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Yun-Hee Bae (Department of Neuroscience, Kyung Hee University) ;
  • Young Taek Oh (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Hyemi Shin (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Hyung Joon Kwon (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Chan Il Kim (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Sung Soo Kim (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Hwan-Geun Choi (Daegu-Gyeongbuk Medical Innovation Foundation (KMEDIhub)) ;
  • Jong Bae Park (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Byoung Dae Lee (Department of Neuroscience, Kyung Hee University)
  • Received : 2024.03.22
  • Accepted : 2024.03.26
  • Published : 2024.08.30
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Abstract

Leucine-rich repeat kinase 2 (LRRK2), a large GTP-regulated serine/threonine kinase, is well-known for its mutations causing late-onset Parkinson's disease. However, the role of LRRK2 in glioblastoma (GBM) carcinogenesis has not yet been fully elucidated. Here, we discovered that LRRK2 was overexpressed in 40% of GBM patients, according to tissue microarray analysis, and high LRRK2 expression correlated with poor prognosis in GBM patients. LRRK2 and stemness factors were highly expressed in various patient-derived GBM stem cells, which are responsible for GBM initiation. Canonical serum-induced differentiation decreased the expression of both LRRK2 and stemness factors. Given that LRRK2 is a key regulator of glioma stem cell (GSC) stemness, we developed DNK72, a novel LRRK2 kinase inhibitor that penetrates the blood-brain barrier. DNK72 binds to the phosphorylation sites of active LRRK2 and dramatically reduced cell proliferation and stemness factors expression in in vitro studies. Orthotopic patient-derived xenograft mouse models demonstrated that LRRK2 inhibition with DNK72 effectively reduced tumor growth and increased survival time. We propose that LRRK2 plays a significant role in regulating the stemness of GSCs and that suppression of LRRK2 kinase activity leads to reduced GBM malignancy and proliferation. In the near future, targeting LRRK2 in patients with high LRRK2-expressing GBM could offer a superior therapeutic strategy and potentially replace current clinical treatment methods.

Keywords

Acknowledgement

This work was supported by grants NRF-2021R1A2C3013315, NRF-2021M3F7A1083230 from National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT. This work was also supported by the research fund of National Cancer Center Graduate School of Cancer Science and Policy (202100020014).

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