Copper ionophore enhanced cisplatin efficiency through DLAT-cuprotosis.

Abstract

Breast cancer is the most prevalent cancer among women globally, and triple-negative breast cancer (TNBC) lacks effective therapeutic strategies. Cuproptosis-related genes (CRGs) are implicated in the progression of breast cancer. Thirteen CRGs have been identified in previous studies. RNA sequencing data from TCGA-BRCA and protein data from the HAP databases indicated that DLAT expression is lower in breast tumor tissues compared to normal tissues. Conversely, high DLAT expression is associated with poor prognosis in patients. However, the specific role and underlying mechanisms of dihydrolipoamide S-acetyltransferase (DLAT) in breast cancer remain largely unexplored. Differential gene and enrichment analyses showed that elevated DLAT expression is involved in the cell cycle, cellular senescence, and the p53 signaling pathway. Furthermore, DLAT expression correlates with immune scores and cellular infiltration. Knockdown of DLAT in breast cancer cells significantly inhibits proliferation, migration and invasion capabilities. Additionally, DLAT positively regulates the expression of genes involved in cell proliferation and epithelial-mesenchymal transition (EMT). Drug sensitivity assays and breast tumor xenograft models demonstrate that the copper ionophore ES-Cu could reverse cisplatin resistance in breast cancer cells by promoting DLAT oligomerization, inducing cuproptosis, and increasing intracellular ROS levels. Therefore, DLAT holds promise as a valuable molecular marker in immunotherapy and as a mediator of cuproptosis, with the potential to enhance the clinical efficacy of breast cancer chemotherapy.