SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress.

摘要: Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of cancer, with poor prognosis and limited treatment options. Hypoxia a key hallmark TNBC. Metabolic adaptation promotes progression TNBC cells that are located within hypoxic tumor regions. However, it not well understood regarding precise molecular mechanisms underlying regulation metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze gene expression profiles in MDA-MB-231 cell line (20% O2 1% O2). Expressions Slc6a8, which encodes creatine transporter protein, were detected tissues quantitative real-time PCR. Immunohistochemistry detect SLC6A8 protein abundances tissues. Clinicopathologic correlation overall survival evaluated chi-square test Kaplan-Meier analysis, respectively. Cell viability assay flow cytometry analysis Annexin V/PI double staining investigate impact SLC6A8-mediated uptake on cells. orthotopic mouse model used evaluate effects vivo. Results aberrantly upregulated drastically overexpressed its level tightly associated advanced TNM stage, higher histological grade worse patients. We found transcriptionally p65/NF-κB mediated accumulation intracellular promoted suppressed apoptosis via maintaining redox homeostasis Furthermore, required facilitate growth xenograft models. Mechanistically, bolstered antioxidant defense reducing mitochondrial activity oxygen consumption rates reduce reactive species, ultimately activating AKT-ERK signaling, activation protected mediating upregulation Ki-67 Bcl-2, downregulation Bax cleaved Caspase-3. Conclusions Our study indicates plays an important role promoting progression, may provide potential therapeutic strategy option for high expressed