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 dynamics are essential for cellular processes, including actomyosin contractility, migration, and autophagy. However, the significance of Ca and Ca channels participating in entosis is unclear. Here, it is shown that intracellular Ca signaling regulates entosis via SEPTIN-Orai1-Ca /CaM-MLCK-actomyosin axis. Intracellular Ca oscillations in entotic cells show spatiotemporal variations during engulfment, mediated by Orai1 Ca 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 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 channel that provides essential Ca signaling and sheds light on the molecular mechanism underlying entosis that involves SEPTIN filaments, Orai1, and MLCK.