DLDH-containing extracellular vesicles from CAFs reduced DOX sensitivity in triple-negative breast cancer

Abstract Chemo-resistance is a major obstacle in the control of advanced triple-negative breast cancer (TNBC). Cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) were critical for tumor progression. Herein, we demonstrated that CAFs/TNBC-derived EVs could suppress doxorubicin (DOX) sensitivity in breast cancer both in vitro and in vivo. The protein array revealed that dihydrolipoamide dehydrogenase (DLDH) was enriched in CAFs/TNBC-derived EVs, which was the E3 component of the 2-oxoglutarate dehydrogenase complex (α-KGDC). EVs-DLDH was transported into mitochondria and enhanced mitochondrial respiration through increasing α-KGDC activity and NADH content. Inhibiting DLDH reduced oxidative phosphorylation (OXPHOS) and CAFs-derived EVs-induced drug resistance in the recipient cells. It was also shown that the EVs-reduced sensitivity of DOX was due to increased drug efflux driven by OXPHOS. Additionally, suppression of ATP-binding cassette transporters or mitochondrial respiration conferred the recipient cells with increased susceptibility to DOX. These results elaborated that CAFs-derived EVs inhibit the DOX sensitivity of TNBC through increasing drug efflux driven by DLDH-induced OXPHOS. Inhibiting EVs-DLDH provides a potential therapeutic application to enhance the responsiveness to chemotherapy in TNBC.