Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer
Abstract Endometrial cancer (EC) is a significant health threat to women, with recurrence after treatment posing a major challenge. While abnormal cholesterol metabolism has been implicated in EC progression, the underlying mechanisms remain unclear. In this study, we identified lanosterol synthase...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02325-y |
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| author | Liangjian Ma Wunan Huang Xiaolei Liang Hongli Li Wei Yu Lexin Liu Yuelin Guan Chang Liu Xiangjun Chen Lidan Hu |
| author_facet | Liangjian Ma Wunan Huang Xiaolei Liang Hongli Li Wei Yu Lexin Liu Yuelin Guan Chang Liu Xiangjun Chen Lidan Hu |
| author_sort | Liangjian Ma |
| collection | DOAJ |
| description | Abstract Endometrial cancer (EC) is a significant health threat to women, with recurrence after treatment posing a major challenge. While abnormal cholesterol metabolism has been implicated in EC progression, the underlying mechanisms remain unclear. In this study, we identified lanosterol synthase (LSS) as a key mediator in cholesterol metabolism associated with EC. We found that LSS is significantly upregulated in EC tissues. Functional assays revealed that LSS promotes cell proliferation and migration, inhibits apoptosis, and drives tumor growth in vivo. Mechanistically, LSS exerts dual effects by accumulating cholesterol esters, thereby enhancing EC cell growth, and activating the MAPK/JNK signaling pathway. Importantly, inhibition of LSS with the specific inhibitor Ro 48-8071 not only reduced EC cell proliferation and suppressed xenograft tumor growth but also inhibited the growth of patient-derived tumor-like cell clusters (PTCs). These findings establish LSS as a novel oncogene in EC, promoting tumor progression through MAPK/JNK signaling activation and cholesterol ester accumulation, and highlight the therapeutic potential of targeting LSS in EC treatment. |
| format | Article |
| id | doaj-art-86dd4d45af1d472e89b11e677f08807c |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-86dd4d45af1d472e89b11e677f08807c2025-02-09T12:12:27ZengNature Publishing GroupCell Death Discovery2058-77162025-02-0111111210.1038/s41420-025-02325-yInhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancerLiangjian Ma0Wunan Huang1Xiaolei Liang2Hongli Li3Wei Yu4Lexin Liu5Yuelin Guan6Chang Liu7Xiangjun Chen8Lidan Hu9The First Clinical Medical College, Lanzhou UniversityThe First Clinical Medical College, Lanzhou UniversityGansu Provincial Clinical Research Center for Gynecological Oncology, The First Hospital of Lanzhou UniversityGansu Provincial Clinical Research Center for Gynecological Oncology, The First Hospital of Lanzhou UniversityEye Center of the Second Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang UniversityThe Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthThe Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthThe First Clinical Medical College, Lanzhou UniversityEye Center of the Second Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang UniversityThe Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthAbstract Endometrial cancer (EC) is a significant health threat to women, with recurrence after treatment posing a major challenge. While abnormal cholesterol metabolism has been implicated in EC progression, the underlying mechanisms remain unclear. In this study, we identified lanosterol synthase (LSS) as a key mediator in cholesterol metabolism associated with EC. We found that LSS is significantly upregulated in EC tissues. Functional assays revealed that LSS promotes cell proliferation and migration, inhibits apoptosis, and drives tumor growth in vivo. Mechanistically, LSS exerts dual effects by accumulating cholesterol esters, thereby enhancing EC cell growth, and activating the MAPK/JNK signaling pathway. Importantly, inhibition of LSS with the specific inhibitor Ro 48-8071 not only reduced EC cell proliferation and suppressed xenograft tumor growth but also inhibited the growth of patient-derived tumor-like cell clusters (PTCs). These findings establish LSS as a novel oncogene in EC, promoting tumor progression through MAPK/JNK signaling activation and cholesterol ester accumulation, and highlight the therapeutic potential of targeting LSS in EC treatment.https://doi.org/10.1038/s41420-025-02325-y |
| spellingShingle | Liangjian Ma Wunan Huang Xiaolei Liang Hongli Li Wei Yu Lexin Liu Yuelin Guan Chang Liu Xiangjun Chen Lidan Hu Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer Cell Death Discovery |
| title | Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer |
| title_full | Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer |
| title_fullStr | Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer |
| title_full_unstemmed | Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer |
| title_short | Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer |
| title_sort | inhibition of lanosterol synthase linking with mapk jnk signaling pathway suppresses endometrial cancer |
| url | https://doi.org/10.1038/s41420-025-02325-y |
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