Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer

Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca(2+) from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity. The disruption of calcium homeostasis induced ER stress, leading to apoptosis. More importantly, the elevated intracellular calcium signals induced autophagy through the activation of the CaMKK-AMPK-mTOR pathway and mitochondrial damage. In two TNBC xenograft mouse models, RL71 also displayed strong efficacy including the inhibition of tumor growth, the reduction of metastasis, as well as the prolongation of survival time. These findings suggest SERCA2 as a previous unknown target candidate for TNBC treatment and support the idea that autophagy inducers could be useful as new therapeutics in TNBC treatment.