A011, a novel small-molecule ligand of σ receptor, potently suppresses breast cancer progression via endoplasmic reticulum stress and autophagy.

Breast cancer has surpassed lung cancer to become the most commonly diagnosed cancer in women worldwide. Sigma-2 (σ) receptor is considered to be a potential therapeutic target for breast cancer because of its high expression in breast cancer cells and low expression in normal breast cells. Many σ ligands have been reported to have excellent anticancer activity, but their mechanism of action has not been fully elucidated. We discovered that A011 had high affinity and selectivity for σ receptor, reduced proliferation in five cancer cell lines, and significantly inhibited the monoclonal formation ability of MCF-7 cells. Furthermore, A011 rapidly increased the levels of intracellular Ca and reactive oxygen species and induced autophagy. Molecular pharmacology studies revealed that A011 induced endoplasmic reticulum stress, activated the PERK-eIF2α-CHOP pathway and inhibited the activation of the PI3K-Akt-mTOR pathway, leading to cell apoptosis. In an in vivo tumor model, A011 showed obvious anti-tumor activity and no significant toxicity. More importantly, our study demonstrated for the first time that endoplasmic reticulum stress is the main mechanism of anti-cancer effects for σ ligands, at least for A011. A011 may potentially be useful as a therapeutic agent for treating breast cancer.