2. Academic Validation
  3. ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy

ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy

  • Cell Death Dis. 2025 Mar 25;16(1):201. doi: 10.1038/s41419-025-07534-y.
Zhengwei Yan # 1 2,  Aidi Huang # 1 3,  Dongwen Ma # 1 3,  Chenao Hong # 1 3,  Shengmiao Zhang 1 3,  Luling He 2,  Hai Rao 4,  Shiwen Luo 5 6
Affiliations

Affiliations

  • 1 Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 2 Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 3 Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 4 Department of Biochemistry, School of Medicine, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China. raoh@sustech.edu.cn.
  • 5 Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China. shiwenluo@ncu.edu.cn.
  • 6 Department of Pathology and Institute of Molecular Pathology, Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China. shiwenluo@ncu.edu.cn.
  • # Contributed equally.
PMID: 40133274 DOI: 10.1038/s41419-025-07534-y
Abstract

Autophagy is a highly conserved cellular process essential for maintaining cellular homeostasis and influencing Cancer development. Lysosomal acidification and autophagosome-lysosome fusion are two important steps of Autophagy degradation that are tightly regulated. Although many key proteins that regulate these two events have been identified, the effector proteins that co-regulate both steps remain to be explored. ATP6AP1, an accessory subunit of V-ATPase, plays a critical role in the assembly and regulation of V-ATPase. However, the function of ATP6AP1 in Autophagy remains unknown, and the role of ATP6AP1 in Cancer is still poorly understood. In this study, we found that ATP6AP1 is overexpressed in luminal breast Cancer tissues and promotes the proliferation and tamoxifen resistance of luminal breast Cancer cells both in vitro and in vivo. We also observed that high ATP6AP1 expression correlates with poor overall patient survival. Our research further revealed that ATP6AP1 enhances tamoxifen resistance by activating Autophagy. Mechanistically, ATP6AP1 promotes Autophagy by regulating both lysosomal acidification and autophagosome-lysosome fusion. Remarkably, ATP6AP1 induces lysosomal acidification through the regulation of V-ATPase assembly and facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS complex. Together, our studies identify ATP6AP1 as a crucial regulator of Autophagy, potentially serving as a valuable prognostic marker or therapeutic target in human luminal breast Cancer.

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