Caerulomycin A disrupts glucose metabolism and triggers ER stress-induced apoptosis in triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a poor prognosis and presents a significant challenge due to its lack of targeted treatment options. This study explored the anticancer potential of Caerulomycin A (Cae A), a natural product derived from marine actinomycetes, specifically TNBC. Cae A was found to specifically inhibit viability and proliferation of TNBC, including 4T1, MDA-MB-231 and MDA-MB-468 cell lines, by inducing apoptosis. Mechanistic studies revealed that the compound exerted its effects by eliciting sustained endoplasmic reticulum (ER) stress and subsequently upregulating C/EBP homologous protein (CHOP) expression, leading to mitochondrial damage mediated apoptosis. The inhibition of ER stress or knockdown of CHOP expression reversed the mitochondrial damage and apoptosis, underscoring the central role of ER stress and CHOP in Cae A's antitumor mechanism. Both OCR and ECAR were suppressed in TNBC cells after Cae A treatment, as evidenced by the weaker mitochondrial respiratory and glycolytic capacities. The decreased energy metabolism may lead to ER stress and subsequent apoptosis. In addition, Cae A displayed remarkable antitumor effect in 4T1 tumor model in vivo without obvious toxicity. Finally, we found that Cae A significantly inhibited the growth of human TNBC organoids. These findings suggested that Cae A might be a potential therapeutic agent for TNBC patients, and that disruption of glucose metabolism and triggering of ER stress-induced apoptosis might be a feasible therapeutic strategy for the treatment of TNBC.