Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy

作者：Bowen Zheng, Fengyuan Qian, Xuehui Wang, Yuying Wang, Baian Zhou, Lin Fang · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2024 · DOI：10.1186/s13046-024-03085-w · 被引用次数：35 · 研究领域：Autophagy in Disease and Therapy、Ubiquitin and proteasome pathways、interferon and immune responses

BACKGROUND: Paclitaxel (PTX) treatment resistance is an important factor leading to poor prognosis in triple-negative breast cancer (TNBC), therefore there is an urgent need to identify new target for combination therapy. Neddylation is a post-translational process that introduces a ubiquitin-like protein called neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Previous studies have found that neddylation is activated in multiple tumors, but its relationship with PTX chemotherapy sensitivity has not been reported. METHODS: Differences in UBC12 and NEDD8 expression levels between PTX-sensitive and PTX-insensitive TNBC tissues were validated using public databases and immunohistochemistry. The in vitro and in vivo functional experiments were used to observe the effect of neddylation inhibition combined with PTX therapy on tumor progression. Co-IP, western blot and PCR assays were used to investigate the molecular mechanisms. Molecular docking was used to simulate the protein binding of UBC12 and TRIM25. Molecular dynamics simulation was used to observe the changes in TRIM25 protein conformation. RESULTS: We found that in TNBC that is insensitive to PTX, NEDD8 and NEDD8 conjugating enzyme UBC12 are highly expressed. Treatment with the NEDD8-activating enzyme (NAE) inhibitor mln4924 or knockdown of UBC12 significantly increased the sensitivity of the tumor to PTX, and this increase in sensitivity is related to UBC12-mediated autophagy activation. Me...