Fig. 1

Disrupted dynamic equilibrium of stromal interaction molecule 1 (STIM1)-calcium release-activated calcium channel protein 1 (ORAI1) and inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ signaling in tumor biology. a In normal cells, STIM1 exists as a single-transmembrane protein in the endoplasmic reticulum (ER). The STIM1 canonical Ca²⁺-binding EF-hand (a conventional helix-loop-helix EF motif) can sensitively detect the depletion of ER luminal Ca²⁺, leading to STIM1 oligomerization and interactions with the C-terminus of ORAI1. The STIM1–ORAI1 complex controls the opening of the Store-operated Ca²⁺ entry (SOCE) channel ORAI1, thereby allowing Ca²⁺ entry. The increased Ca²⁺ in the ER can enter into the mitochondria via IP₃Rs, leading to mitochondrial Ca²⁺ overload and indirectly causing apoptosis. The mitochondrial outer membrane permeabilization (MOMP) is considered a critical step during the point-of-no-return apoptosis in the mitochondria. b In prostate cancer cells, an increase in the level of the endogenous ORAI3 protein causes the association of ORAI3 with ORAI1 to form a heteromultimeric channel that can alter the ORAI3-ORAI1 ratio. These functions represent an oncogenic switch that promotes prostate cancer cell proliferation and confers apoptosis resistance. c STIM1–ORAI1-mediated Ca²⁺ signaling accelerates tumor cell migration through controlling focal adhesion (FA) turnover and actomyosin contractility. The STIM1–ORAI1-mediated Ca²⁺ influx regulates actomyosin formation and increases its contractile force. STIM1–ORAI1 induces the Ca²⁺ influx and promotes the cleavage of FA proteins. The red represents all of the factors involved in resistance to apoptosis, and the blue represents all of the factors that promote apoptosis. d Bcl-2 is a representative anti-apoptotic protein that interacts with IP₃R via its N-terminal BH4 domain. Then, Bcl-2 inhibits the Ca²⁺ flux into the mitochondria, leading to mitochondrial Ca²⁺ deficiency and preventing cancer cell apoptosis. The deficient Ca²⁺ can break MOMP and finally prevent cancer cell apoptosis