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
104P - Hypomethylated immune gene promoters as potential biomarkers in oral and oropharyngeal cancer
Presenter: Petra Anić
Session: Cocktail & Poster Display session
Resources:
Abstract
105P - Implementation of technical improvements in cfMeDIP-Seq library preparation
Presenter: Martina Dameri
Session: Cocktail & Poster Display session
Resources:
Abstract
106P - Clinical application of next-generation sequencing in metastatic colorectal cancer (mCRC): Experience from a comprehensive cancer centre
Presenter: David Lluís Garulo
Session: Cocktail & Poster Display session
Resources:
Abstract
107P - Unveiling mismatch repair deficiency (dMMR) and microsatellite-instability high (MSI-H) detection in cancer patients (pt) using a next-generation sequencing (NGS)-based molecular pre-screening program (MPP)
Presenter: Lucia Notario Rincon
Session: Cocktail & Poster Display session
Resources:
Abstract
108P - Validation and implementation of a large NGS panel to test liquid biopsies from patients with suspected advanced non-small cell lung cancer (NSCLC) in an NHS genomic laboratory for the QuicDNA biomarker study
Presenter: Rachel Dodds
Session: Cocktail & Poster Display session
Resources:
Abstract
109P - A multiomic, single-cell measurable residual disease (scMRD) assay for phasing DNA mutations and surface immunophenotypes
Presenter: Simone Formisano
Session: Cocktail & Poster Display session
Resources:
Abstract
110P - Multicellular three-dimensional tumor spheroid of nasopharyngeal carcinoma
Presenter: Shiau Chuen Cheah
Session: Cocktail & Poster Display session
Resources:
Abstract
111P - Development of digital PCR for accurate measurement of HER2 amplification in 184 gastric cancer patients
Presenter: So Young Kang
Session: Cocktail & Poster Display session
Resources:
Abstract
112P - A novel methylation-sensitive assay for early detection of hepatocellular carcinoma to improve surveillance
Presenter: Jeong Sil Ha
Session: Cocktail & Poster Display session
Resources:
Abstract
113P - Evaluation of effects of tissue preservation methods on the proteome abundance through deep proteomics of breast cancer tissue
Presenter: Shashwati parihari
Session: Cocktail & Poster Display session
Resources:
Abstract