Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization

• Published in: Cancer letters Vol. 587; p. 216732
• Main Authors: Xiong, Hanchu, Zhai, Yanan, Meng, Yimei, Wu, Zhuazhua, Qiu, Anchen, Cai, Yu, Wang, Geyi, Yang, Liu
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10.04.2024
• Subjects: Acidosis; Breast cancer; Ferroptosis; Macrophage; Metformin; Ubiquitination; Ferroptosis; Ubiquitination; Breast cancer; Metformin; Acidosis; Macrophage
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2024.216732

Acidosis is involved in multiple pathways in tumor cells and immune cells among the tumor microenvironment (TME). Ferroptosis is a nonapoptotic and iron-dependent form of cell death characterized by accumulation of lipid peroxidation involved in various cancers. The role of ferroptosis in the breast cancer (BC) acidic microenvironment remains unrevealed. Here, we reported that short-term acidosis induced ferroptosis of BC cells in the zinc finger AN1-type domain 5 (ZFAND5)/solute carrier family 3 member 2 (SLC3A2) dependent manner to suppress tumor growth using in silico and multiple biological methods. Mechanistically, we demonstrated that short-term acidosis increased total/lipid reactive oxygen species (ROS) level, decreased glutathione (GSH) level and induced the morphological changes of mitochondria. Specifically, acidosis restrained the protein stability of SLC3A2 by promoting its ubiquitination process. The prognostic analysis showed that higher expression of ZFAND5 and lower expression of SLC3A2 were correlated with longer overall survival of BC patients, respectively. Furthermore, in combination with ferroptosis agonist metformin, short-term acidosis could synergistically inhibit viability and enhance the ferroptosis of BC cells. Meanwhile, by the exploration of immune cells, short-term acidosis also induced M1 macrophage polarization, triggering processes of phagocytosis and ferroptosis in BC cells. This study demonstrated that short-term acidosis induced BC cell ferroptosis through ZFAND5/SLC3A2 signaling axis and promoted phagocytosis and ferroptosis of BC cells with M1 macrophage polarization, which might be a new mechanism for BC therapy. •Short-term acidosis can induce cell death of breast cancer through ferroptosis.•Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization.•SLC3A2 is a newly discovered ubiquitination substrate of ZFAND5 and the ubiquitination site of SLC3A2 is K29/33/48.•Higher expression of ZFAND5 and lower expression of SLC3A2 are associated with better survival of breast cancer patients.•Synergistic effect of metformin and acidosis effectively promotes breast cancer cells ferroptosis in vitro and in vivo.