Anti-NOTCH1 therapy with OMP-52 M51 inhibits salivary adenoid cystic carcinoma by depressing epithelial-mesenchymal transition (EMT) process and inducing ferroptosis

Abstract

Salivary adenoid cystic carcinoma (ACC) is a common type of salivary gland cancer, and the mechanisms underlying its progression still remain poorly understood without efficient therapies. NOTCH1, an evolutionally conserved cell-cell signaling pathway, is involved in the progression of ACC. In our study, we attempted to explore whether NOTCH1 suppression using the monoclonal anti-NOTCH1 antibody OMP-52 M51 could be of potential for ACC treatment. Here, we identified NOTCH1 elevation in human ACC tissues compared with the matched normal samples. Patients with metastasis expressed much higher NOTCH1. We then found that OMP-52 M51 markedly reduced the expression of NOTCH1 and its intracellular active form NICD1 (NOTCH1 intracellular domain). Importantly, OMP-52 M51 markedly reduced the proliferation, migration and invasion of ACC cells. RNA-Seq and in vitro studies further showed that OMP-52 M51 significantly induced ferroptosis in ACC cells, indicated by the increased cellular malondialdehyde (MDA), iron contents and lipid ROS production, and decreased glutathione (GSH) levels. Further, remarkable glutathione peroxidase 4 (GPX4) reduction was detected in ACC cells with OMP-52 M51 treatment. However, promoting NOTCH1 expression markedly abolished the function of OMP-52 M51 to induce ferroptosis. Intriguingly, low-dose OMP-52 M51 strongly facilitated the capacity of ferroptosis inducer erastin to trigger ferroptotic cell death, revealing that OMP-52 M51 could improve the sensitivity of ACC cells to ferroptosis. In vivo, OMP-52 M51 administration suppressed tumor growth and induced ferroptosis in the constructed ACC xenograft mouse model. Collectively, our findings demonstrated that NOTCH1 inhibition by OMP-52 M51 represses the proliferation and epithelial-mesenchymal transition (EMT) in ACCs, and promotes ferroptosis, revealing the potential therapeutical application of OMP-52 M51 in ACC.