TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway

作者：Chun Chen, Longyang Jin, Hong Wan, Hu Liu, Shuping Zhang, Gang Shen, Jiao Gong, Yong Zhu · 发表于：Cell Death Discovery · 年份：2025 · DOI：10.1038/s41420-025-02477-x · 被引用次数：7 · 研究领域：Autophagy in Disease and Therapy、Cell death mechanisms and regulation、Ubiquitin and proteasome pathways

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 vi...