TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway
Abstract Drug resistance is a major obstacle to the effective treatment of colorectal cancer (CRC). However, the underlying mechanism remains unclear. In this study, we investigated the function and mechanism of TIPE3 in drug resistance of CRC. TIPE3 expression in clinical samples and CRC cell lines...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02477-x |
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| _version_ | 1850170854175932416 |
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| author | Chun Chen Longyang Jin Hong Wan Hu Liu Shuping Zhang Gang Shen Jiao Gong Yong Zhu |
| author_facet | Chun Chen Longyang Jin Hong Wan Hu Liu Shuping Zhang Gang Shen Jiao Gong Yong Zhu |
| author_sort | Chun Chen |
| collection | DOAJ |
| description | Abstract Drug resistance is a major obstacle to the effective treatment of colorectal cancer (CRC). However, the underlying mechanism remains unclear. In this study, we investigated the function and mechanism of TIPE3 in drug resistance of CRC. TIPE3 expression in clinical samples and CRC cell lines was detected using qPCR. CCK-8 and colony formation assays were employed to analyze the proliferation of CRC cells. The apoptosis of CRC cells was analyzed using flow cytometry, and autophagy of CRC cells was detected using western blotting, transmission electron microscopy, and immunofluorescence. Moreover, the relationship between USP19 and Beclin1 was detected using co-immunoprecipitation. CRC cells that had been transfected with OE-TIPE3 were co-cultured with macrophages (THP-1 cells induced by PMA), to create a model of TIPE3 overexpression in macrophage M2 polarization. Additionally, a nude mouse tumor model was established. After chemotherapy, tumor apoptosis was detected using the TUNEL assay, and autophagy levels were measured using immunofluorescence, immunohistochemistry, and western blotting. TIPE3 expression was increased in both CRC tumors and cell lines. TIPE3 overexpression substantially promoted drug resistance in CRC in vivo and in vitro. Furthermore, TIPE3 upregulated USP19 protein expression, which accelerated autophagy. In addition, co-immunoprecipitation showed an interaction between USP19 and Beclin1. TIPE3 increased drug resistance by enhancing CRC cell autophagy via the USP19/Beclin1 pathway and stimulating macrophage polarization towards the M2-type. Thus, TIPE3 could serve as a potential target for the development of novel strategies to overcome chemoresistance. |
| format | Article |
| id | doaj-art-e6f205518a744e35a85bbe61fdd14005 |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death Discovery |
| spelling | doaj-art-e6f205518a744e35a85bbe61fdd140052025-08-20T02:20:23ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111210.1038/s41420-025-02477-xTIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathwayChun Chen0Longyang Jin1Hong Wan2Hu Liu3Shuping Zhang4Gang Shen5Jiao Gong6Yong Zhu7Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen UniversityDepartment of General Surgery, The First Affiliated Hospital of Anhui Medical UniversityDepartment of General Surgery, The First Affiliated Hospital of Anhui Medical UniversityDepartment of Emergency Surgery, First Affiliated Hospital of Anhui Medical University; Anhui Public Health Clinical CenterDepartment of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen UniversityDepartment of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen UniversityDepartment of General Surgery, The First Affiliated Hospital of Anhui Medical UniversityAbstract Drug resistance is a major obstacle to the effective treatment of colorectal cancer (CRC). However, the underlying mechanism remains unclear. In this study, we investigated the function and mechanism of TIPE3 in drug resistance of CRC. TIPE3 expression in clinical samples and CRC cell lines was detected using qPCR. CCK-8 and colony formation assays were employed to analyze the proliferation of CRC cells. The apoptosis of CRC cells was analyzed using flow cytometry, and autophagy of CRC cells was detected using western blotting, transmission electron microscopy, and immunofluorescence. Moreover, the relationship between USP19 and Beclin1 was detected using co-immunoprecipitation. CRC cells that had been transfected with OE-TIPE3 were co-cultured with macrophages (THP-1 cells induced by PMA), to create a model of TIPE3 overexpression in macrophage M2 polarization. Additionally, a nude mouse tumor model was established. After chemotherapy, tumor apoptosis was detected using the TUNEL assay, and autophagy levels were measured using immunofluorescence, immunohistochemistry, and western blotting. TIPE3 expression was increased in both CRC tumors and cell lines. TIPE3 overexpression substantially promoted drug resistance in CRC in vivo and in vitro. Furthermore, TIPE3 upregulated USP19 protein expression, which accelerated autophagy. In addition, co-immunoprecipitation showed an interaction between USP19 and Beclin1. TIPE3 increased drug resistance by enhancing CRC cell autophagy via the USP19/Beclin1 pathway and stimulating macrophage polarization towards the M2-type. Thus, TIPE3 could serve as a potential target for the development of novel strategies to overcome chemoresistance.https://doi.org/10.1038/s41420-025-02477-x |
| spellingShingle | Chun Chen Longyang Jin Hong Wan Hu Liu Shuping Zhang Gang Shen Jiao Gong Yong Zhu TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway Cell Death Discovery |
| title | TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway |
| title_full | TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway |
| title_fullStr | TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway |
| title_full_unstemmed | TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway |
| title_short | TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway |
| title_sort | tipe3 promotes drug resistance in colorectal cancer by enhancing autophagy via the usp19 beclin1 pathway |
| url | https://doi.org/10.1038/s41420-025-02477-x |
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