Niclosamide suppresses breast cancer progression and enhances paclitaxel sensitivity by targeting the ATP6AP1-YY1-XIAP axis.

Authors

Xin-Yuan Sun, Xiao-Ya Wan, Shi-Jun Cao, Rong Gong, Shi-Long Jiang, Yi-Zhi Li, Yi-Ning Cheng, Yun-Gui Li, Ting Jiang, Zhong-Yuan Xiang, Yan Cheng

Published in

Acta pharmacologica Sinica. Sep 22, 2026. Epub Sep 22, 2026.

Abstract

ATP6AP1, a key accessory subunit of the vacuolar H⁺-ATPase (V-ATPase) complex responsible for organelle acidification, has emerged as a potential cancer driver. Numerous studies have shown that ATP6AP1 is significantly upregulated in breast cancer, and its high expression is associated with poor prognosis. However, the specific functions and underlying mechanisms of ATP6AP1 in breast cancer progression remain unclear. In the present study, ATP6AP1 was demonstrated to enhance the malignant phenotype of breast cancer cells by upregulating XIAP expression. YY1 was further identified as a novel transcription factor that regulates XIAP, and ATP6AP1 was shown to directly interact with YY1, thereby stabilizing YY1 protein levels and subsequently promoting XIAP expression. In addition, ATP6AP1 silencing markedly increased the sensitivity of breast cancer cells to paclitaxel. Through screening of an FDA-approved drug library, niclosamide was identified as a novel degrader of ATP6AP1. Niclosamide bound to ATP6AP1, reduced its protein stability, and consequently downregulated its expression. Moreover, niclosamide inhibited the proliferation, migration, and invasion of breast cancer cells while promoting apoptosis through targeted degradation of ATP6AP1. Furthermore, niclosamide significantly enhanced the sensitivity of breast cancer cells to paclitaxel by targeting the ATP6AP1-YY1-XIAP axis. Taken together, these findings demonstrated that ATP6AP1 promotes breast cancer progression through activation of the YY1-XIAP signaling axis. Niclosamide was also identified as a promising therapeutic agent targeting ATP6AP1, thereby providing a potential therapeutic strategy for breast cancer treatment.

PMID:
42773187
Bibliographic data and abstract were imported from PubMed on 23 Sep 2026.

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