USP51/GRP78/ABCB1 axis confers chemoresistance through decreasing doxorubicin accumulation in triple-negative breast cancer cells.

Yang OU; Kun ZHANG; Qiuying SHUAI; Chenyang WANG; Huayu HU; Lixia CAO; Chunchun QI; Min GUO; Zhaoxian LI; Jie SHI; Yuxin LIU; Siyu ZUO; Xiao CHEN; Yanjing WANG; Mengdan FENG; Hang WANG; Peiqing SUN; Yi SHI; Guang YANG; Shuang YANG

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USP51/GRP78/ABCB1 axis confers chemoresistance through decreasing doxorubicin accumulation in triple-negative breast cancer cells.

Author: Yang OU ¹ ; Kun ZHANG ¹ ; Qiuying SHUAI ¹ ; Chenyang WANG ¹ ; Huayu HU ¹ ; Lixia CAO ¹ ; Chunchun QI ¹ ; Min GUO ¹ ; Zhaoxian LI ¹ ; Jie SHI ¹ ; Yuxin LIU ¹ ; Siyu ZUO ¹ ; Xiao CHEN ¹ ; Yanjing WANG ¹ ; Mengdan FENG ¹ ; Hang WANG ¹ ; Peiqing SUN ² ; Yi SHI ¹ ; Guang YANG ¹ ; Shuang YANG ¹
Author Information

1. Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, College of Pharmacy, Nankai University, Tianjin 300071, China.
2. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Publication Type:Journal Article
Keywords: ABCB1; Chemoresistance; Deubiquitinating enzyme; Doxorubicin; GRP78; Inhibitor; TNBC; USP51
From: Acta Pharmaceutica Sinica B 2025;15(5):2593-2611
CountryChina
Language:English
Abstract: Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.