Orai1 is an Entotic Ca(2+) Channel for Non‐Apoptotic Cell Death, Entosis in Cancer Development

Entosis is a non‐apoptotic cell death process that forms characteristic cell‐in‐cell structures in cancers, killing invading cells. Intracellular Ca(2+) dynamics are essential for cellular processes, including actomyosin contractility, migration, and autophagy. However, the significance of Ca(2+) and Ca(2+) channels participating in entosis is unclear. Here, it is shown that intracellular Ca(2+) signaling regulates entosis via SEPTIN‐Orai1‐Ca(2+)/CaM‐MLCK‐actomyosin axis. Intracellular Ca(2+) oscillations in entotic cells show spatiotemporal variations during engulfment, mediated by Orai1 Ca(2+) channels in plasma membranes. SEPTIN controlled polarized distribution of Orai1 for local MLCK activation, resulting in MLC phosphorylation and actomyosin contraction, leads to internalization of invasive cells. Ca(2+) chelators and SEPTIN, Orai1, and MLCK inhibitors suppress entosis. This study identifies potential targets for treating entosis‐associated tumors, showing that Orai1 is an entotic Ca(2+) channel that provides essential Ca(2+) signaling and sheds light on the molecular mechanism underlying entosis that involves SEPTIN filaments, Orai1, and MLCK.