Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma
Abstract Lenvatinib, an approved first-line regimen, has been widely applied in hepatocellular carcinoma (HCC). However, clinical response towards Lenvatinib was limited, emphasizing the importance of understanding the underlying mechanism of its resistance. Herein, we employed integrated bioinforma...
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| Format: | Article |
| Language: | English |
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Springer
2024-12-01
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| Series: | Molecular Biomedicine |
| Online Access: | https://doi.org/10.1186/s43556-024-00242-7 |
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| author | Xiaolu Ma Kaixia Zhou Tianqing Yan Ling Hu Suhong Xie Hui Zheng Ying Tong Heng Zhang Yanchun Wang Zhiyun Gong Cuncun Chen Yanan Tian Lin Guo Renquan Lu |
| author_facet | Xiaolu Ma Kaixia Zhou Tianqing Yan Ling Hu Suhong Xie Hui Zheng Ying Tong Heng Zhang Yanchun Wang Zhiyun Gong Cuncun Chen Yanan Tian Lin Guo Renquan Lu |
| author_sort | Xiaolu Ma |
| collection | DOAJ |
| description | Abstract Lenvatinib, an approved first-line regimen, has been widely applied in hepatocellular carcinoma (HCC). However, clinical response towards Lenvatinib was limited, emphasizing the importance of understanding the underlying mechanism of its resistance. Herein, we employed integrated bioinformatic analysis to identify calpain-2 (CAPN2) as a novel key regulator for Lenvatinib resistance in HCC, and its expression greatly increased in both Lenvatinib-resistant HCC cell lines and clinical samples. Further in vitro and in vivo experiments indicated that knocking down CAPN2 greatly sensitized HCC cells to Lenvatinib treatment, while overexpression of CAPN2 achieved opposite effects in a Lenvatinib-sensitive HCC cell line. Interestingly, we observed a close relationship between CAPN2 expression and cancer stem cell (CSC) traits in HCC cells, evidenced by impaired sphere-forming and CSC-related marker expressions after CAPN2 knockdown, and verse vice. Mechanistically, we strikingly discovered that CAPN2 exerted its function by both enzyme-dependent and enzyme-independent manner simultaneously: activating β-Catenin signaling through its enzyme activity, and preventing GLI1/GLI2 degradation through direct binding to YWHAE in an enzyme-independent manner, which disrupting the association between YWHAE and GLI1/GLI2 to inhibit YWHAE-induced degradation of GLIs. Notably, further co-immunoprecipitation assays revealed that YWHAE could promote the protein stability of CAPN2 via recruiting a deubiquitinase COPS5 to prevent ubiquitination-induced degradation of CAPN2. In summary, our data demonstrated that CAPN2 promoted Lenvatinib resistance via both catalytic activity-dependent and -independent approaches. Reducing CAPN2 protein rather than inhibiting its activity might be a promising strategy to improve Lenvatinib treatment efficiency in HCC. |
| format | Article |
| id | doaj-art-b832080096c44c9fbec6a4577a0b62b6 |
| institution | Kabale University |
| issn | 2662-8651 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Springer |
| record_format | Article |
| series | Molecular Biomedicine |
| spelling | doaj-art-b832080096c44c9fbec6a4577a0b62b62025-01-05T12:05:07ZengSpringerMolecular Biomedicine2662-86512024-12-015111810.1186/s43556-024-00242-7Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinomaXiaolu Ma0Kaixia Zhou1Tianqing Yan2Ling Hu3Suhong Xie4Hui Zheng5Ying Tong6Heng Zhang7Yanchun Wang8Zhiyun Gong9Cuncun Chen10Yanan Tian11Lin Guo12Renquan Lu13Department of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityDepartment of Clinical Laboratory, Shanghai Cancer Center, Fudan UniversityAbstract Lenvatinib, an approved first-line regimen, has been widely applied in hepatocellular carcinoma (HCC). However, clinical response towards Lenvatinib was limited, emphasizing the importance of understanding the underlying mechanism of its resistance. Herein, we employed integrated bioinformatic analysis to identify calpain-2 (CAPN2) as a novel key regulator for Lenvatinib resistance in HCC, and its expression greatly increased in both Lenvatinib-resistant HCC cell lines and clinical samples. Further in vitro and in vivo experiments indicated that knocking down CAPN2 greatly sensitized HCC cells to Lenvatinib treatment, while overexpression of CAPN2 achieved opposite effects in a Lenvatinib-sensitive HCC cell line. Interestingly, we observed a close relationship between CAPN2 expression and cancer stem cell (CSC) traits in HCC cells, evidenced by impaired sphere-forming and CSC-related marker expressions after CAPN2 knockdown, and verse vice. Mechanistically, we strikingly discovered that CAPN2 exerted its function by both enzyme-dependent and enzyme-independent manner simultaneously: activating β-Catenin signaling through its enzyme activity, and preventing GLI1/GLI2 degradation through direct binding to YWHAE in an enzyme-independent manner, which disrupting the association between YWHAE and GLI1/GLI2 to inhibit YWHAE-induced degradation of GLIs. Notably, further co-immunoprecipitation assays revealed that YWHAE could promote the protein stability of CAPN2 via recruiting a deubiquitinase COPS5 to prevent ubiquitination-induced degradation of CAPN2. In summary, our data demonstrated that CAPN2 promoted Lenvatinib resistance via both catalytic activity-dependent and -independent approaches. Reducing CAPN2 protein rather than inhibiting its activity might be a promising strategy to improve Lenvatinib treatment efficiency in HCC.https://doi.org/10.1186/s43556-024-00242-7 |
| spellingShingle | Xiaolu Ma Kaixia Zhou Tianqing Yan Ling Hu Suhong Xie Hui Zheng Ying Tong Heng Zhang Yanchun Wang Zhiyun Gong Cuncun Chen Yanan Tian Lin Guo Renquan Lu Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma Molecular Biomedicine |
| title | Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma |
| title_full | Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma |
| title_fullStr | Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma |
| title_full_unstemmed | Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma |
| title_short | Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma |
| title_sort | calpain 2 promotes lenvatinib resistance and cancer stem cell traits via both proteolysis dependent and independent approach in hepatocellular carcinoma |
| url | https://doi.org/10.1186/s43556-024-00242-7 |
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