Abstract 64P
Background
Acidosis has been found to have multiple effects on tumor cells and immune cells among the tumor microenvironment. Ferroptosis is a nonapoptotic and iron-dependent form of cell death characterized by the accumulation of lipid peroxidation involved in various cancers. However, recent ferroptosis research in the breast cancer (BC) acidic microenvironment context remains limited. Given the evidence indicating the potential anti-cancer efficacy of metformin, the exact mechanism related to acidic tumor microenvironment has not yet been fully elucidated.
Methods
The ZFAND5/SLC3A2 axis was verified by in silico and multiple biological experiments and the ubiquitination of SLC3A2 was detected by immunoprecipitation. The level of ferroptosis was detected by the total/lipid reactive oxygen species (ROS) and glutathione (GSH) levels in BC cells, and the morphological changes of mitochondria were determined by transmission electron microscope. The mechanism in vivo was demonstrated by the in situ implantation tumor model in nude mice. Relation of BC cells and macrophages was determined by co-culture, western blot, flow cytometry and immunofluorescence.
Results
Acidosis induced ferroptosis in the ZFAND5/SLC3A2 independent manner to suppress tumor growth. Mechanistically, we demonstrated that acidosis increased total/lipid ROS level, decreased GSH level and induced the morphological changes of mitochondria. Specifically, acidosis restrained the protein stability of SLC3A2 by promoting its ubiquitination process. Furthermore, acidosis combined with metformin or macrophages, could work in a synergistic manner to suppress the proliferation and enhance the ferroptosis of BC cells.
Conclusions
This study demonstrated that the combination of acidosis and metformin with macrophages to induce ferroptosis might be a novel mechanism underlying its anti-BC effect. Additionally, we validated that SLC3A2 was a new ZFAND5 mediated ubiquitination substrate and proposed that targeting the ZFAND5/SLC3A2 axis could be a novel therapeutic strategy for BC patients.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
The author.
Funding
National Natural Science Foundation of China.
Disclosure
The author has declared no conflicts of interest.
Resources from the same session
125P - Combination of navitoclax with alpelisib and trametinib to synergistically impair cell viability in high-grade ovarian cancer
Presenter: Lisa Wozelka-Oltjan
Session: Cocktail & Poster Display session
Resources:
Abstract
126P - Effect of sequential antitumoral treatment with immune checkpoint blockade and tyrosine kinase inhibitors in hepatocellular carcinoma
Presenter: Vincenza Ciaramella
Session: Cocktail & Poster Display session
Resources:
Abstract
127P - Novel bone-targeting of activatable sirolimus for targeted therapy of bone-resident cancers
Presenter: Alistare Sadra
Session: Cocktail & Poster Display session
Resources:
Abstract
128P - Network medicine approach identifies small molecule drugs as immune checkpoint inhibitors repurposable for rectal cancer
Presenter: Faheem Ahmed
Session: Cocktail & Poster Display session
Resources:
Abstract
129P - Repurposing existing therapies for adrenal cancer: Unlocking new possibilities
Presenter: Anupama Samantasinghar
Session: Cocktail & Poster Display session
Resources:
Abstract
130P - Restoration of the mutant p53 protein upon treatment with small molecule modulators
Presenter: Elvina Gilyazova
Session: Cocktail & Poster Display session
Resources:
Abstract
131P - Trop 2 and its overexpression in metastatic colorectal cancer patients (mCRCp): Biological, clinical and therapeutic implications
Presenter: Andrea Mancuso Petricca
Session: Cocktail & Poster Display session
Resources:
Abstract
132P - Novel small molecule modulators for activation of mutant tumor suppressor p53
Presenter: Damir Davletshin
Session: Cocktail & Poster Display session
Resources:
Abstract
133P - Cytotoxic efficacy of artificial vesicles obtained from CAR-T cells by ultrasonication
Presenter: Ekaterina Zmievskaya
Session: Cocktail & Poster Display session
Resources:
Abstract
134P - Doxorubicin and olaparib (OLA) synergism in high-grade serous ovarian (HGOC) and triple-negative breast cancer (TNBC) cell lines with olaparib-resistance
Presenter: Jose Alejandro Perez Fidalgo
Session: Cocktail & Poster Display session
Resources:
Abstract