Orai1 is an Entotic Ca2+ 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 Ca2+ dynamics are essential for cellular processes, including actomyosin contractility, migration, and autophagy. However, the significance of Ca2+ and Ca2+ channels participating in entosis is unclear. Here, it is shown that intracellular Ca2+ signaling regulates entosis via SEPTIN-Orai1-Ca2+/CaM-MLCK-actomyosin axis. Intracellular Ca2+ oscillations in entotic cells show spatiotemporal variations during engulfment, mediated by Orai1 Ca2+ 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. Ca2+ 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 Ca2+ channel that provides essential Ca2+ signaling and sheds light on the molecular mechanism underlying entosis that involves SEPTIN filaments, Orai1, and MLCK.

Automated summary

Intracellular calcium signaling regulates entosis through the SEPTIN-Orai1-Ca2+/CaM-MLCK-actomyosin axis. Orai1 calcium channels mediate intracellular calcium oscillations in entotic cells, and SEPTIN controls the polarized distribution of Orai1 for MLCK activation, resulting in actomyosin contraction and internalization of invasive cells. Calcium chelators and inhibitors of SEPTIN, Orai1, and MLCK can suppress entosis.