Targeting cuproptosis by zinc pyrithione in triple-negative breast cancer

Xu Yang; Li Deng; Xianhong Diao; Siyuan Yang; Li Zou; Qin Yang; Jian Li; Jianyun Nie; Lina Zhao; Baowei Jiao

doi:10.1016/j.isci.2023.108218

Targeting cuproptosis by zinc pyrithione in triple-negative breast cancer

iScience. 2023 Oct 16;26(11):108218. doi: 10.1016/j.isci.2023.108218. eCollection 2023 Nov 17.

Authors

Xu Yang^{1

2}, Li Deng³, Xianhong Diao^{1

2}, Siyuan Yang³, Li Zou¹, Qin Yang¹, Jian Li⁴, Jianyun Nie³, Lina Zhao¹, Baowei Jiao^{1

5}

Affiliations

¹ National Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
² Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650201, China.
³ Department of Breast Cancer, Third Affiliated Hospital, Kunming Medical University, 519 Kunzhou Road, Kunming, Yunnan 650118, China.
⁴ Institutional Center for Shared Technologies and Facilities, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
⁵ KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650203, China.

Abstract

Triple-negative breast cancer (TNBC) poses a considerable challenge due to its aggressive nature. Notably, metal ion-induced cell death, such as ferroptosis, has garnered significant attention and demonstrated potential implications for cancer. Recently, cuproptosis, a potent cell death pathway reliant on copper, has been identified. However, whether cuproptosis can be targeted for cancer treatment remains uncertain. Here, we screened the US Food and Drug Administration (FDA)-approved drug library and identified zinc pyrithione (ZnPT) as a compound that significantly inhibited TNBC progression. RNA sequencing revealed that ZnPT disrupted copper homeostasis. Furthermore, ZnPT facilitated the oligomerization of dihydrolipoamide S-acetyltransferase, a landmark molecule of cuproptosis. Clinically, high expression levels of cuproptosis-related proteins were significantly correlated with poor prognosis in TNBC patients. Collectively, these findings indicate that ZnPT can induce cell death by targeting and disrupting copper homeostasis, providing a potential experimental foundation for exploring cuproptosis as a target in drug discovery for TNBC patients.

Keywords: Cancer; Cell biology; Molecular biology.