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Fig. 1 | Chinese Journal of Cancer

Fig. 1

From: Altered expression of stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in cancer: will they become a new battlefield for oncotherapy?

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

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