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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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
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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| Summary: | 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. |
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| ISSN: | 2058-7716 |