Int J Biol Sci 2022; 18(7):2949-2961. doi:10.7150/ijbs.68438 This issue

Research Paper

Mitochondrial Protein UCP1 Inhibits the Malignant Behaviors of Triple-negative Breast Cancer through Activation of Mitophagy and Pyroptosis

Jing Xia1, Changbin Chu1, Wanqing Li1, Hong Chen1, Wenhua Xie1, Rui Cheng1, Kai Hu2, Xi Li1✉

1. Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China
2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Xia J, Chu C, Li W, Chen H, Xie W, Cheng R, Hu K, Li X. Mitochondrial Protein UCP1 Inhibits the Malignant Behaviors of Triple-negative Breast Cancer through Activation of Mitophagy and Pyroptosis. Int J Biol Sci 2022; 18(7):2949-2961. doi:10.7150/ijbs.68438. Available from https://www.ijbs.com/v18p2949.htm

File import instruction

Abstract

Graphic abstract

Triple-negative breast cancer (TNBC) is a massive threat to women's health due to its high morbidity, malignancy, and the refractory, effective therapeutic option of TNBC is still deficient. The mitochondrial protein showed therapeutic potential on breast cancer, whereas the mechanism and downstream pathway of mitochondrial uncoupling protein 1 (UCP1) was not fully elucidated. We found that UCP1 was negatively regulated to the process of TNBC. Overexpressing UCP1 could inhibit the proliferation and metastasis of TNBC, meanwhile inducing the mitochondrial swelling and activation of mitophagy in vitro. Mitophagy activation was then assessed to elucidate whether it was downstream of UCP1 in TNBC metastasis. GSDME is the core of pyroptosis. We found that GSDME was activated in the TNBC cells when UCP1 levels were high. It regulates TNBC cell proliferation potential instead of the apoptosis process in vitro and in vivo. Our results suggested that UCP1 could inhibit the process of TNBC by activating mitophagy and pyroptosis. Impaired activation of mitophagy weakens the regulation effect of UCP1 on metastasis of TNBC, similar to the impairment of GSDME activation on the proliferation regulation of UCP1 on TNBC. UCP1 might be a novel therapeutic target of TNBC.

Keywords: UCP1, Mitophagy, Pyroptosis, GSDME, Triple-negative breast cancer