The store-operated calcium channels in cancer metastasis: from cell migration, invasion to metastatic colonization

Abstract

Store-operated calcium entry (SOCE) is the predominant calcium entry mechanism in most cancer cells. SOCE is mediated by the endoplasmic reticulum calcium sensor STIMs (STIM1 and 2) and plasma membrane channel forming unit Orais (Orai 1-3). In recent years there is increasing evidence indicating that SOCE in cancer cells is dysregulated to promote cancer cell migration, invasion and metastasis. The overexpression of STIM and Orai proteins has been reported to correlate with the metastatic progression of various cancers. The hyperactive SOCE may promote metastatic dissemination and colonization by reorganizing the actin cytoskeleton, degrading the extracellular matrix and remodeling the tumor microenvironment. Here we discuss how these recent progresses provide novel insights to our understanding of tumor metastasis.

Figure 1

Upon Ca2⁺ depletion from the ER lumen, STIM1 molecules on the ER membrane oligomerize and translocate to the junctions between the ER and plasma membrane. At the ER-PM junction, STIM1 oligomers interact with Orai1 channels to activate SOCE. The hyperactive SOCE in cancer cells promotes metastasis by facilitating focal adhesion turnover and invodopodia formation. The elevation of cytosolic Ca2⁺ may facilitate focal adhesion turnover through small GTPases Ras/Rac. The binding of Ca2⁺/calmodulin to IQ-motif containing guanine nucleotide exchanges factors (e.g. RasGRF1 and 2) promotes the GTP binding and Ras/Rac activation. Cytosolic Ca2⁺ may also facilitate focal adhesion turnover through Ca2⁺-activated protease calpain, which cleave many focal adhesion proteins. The cytosolic Ca2⁺ may also activate Pyk2 through Ca2⁺/calmodulin, which binds to an IQ motif at the FERM domain of Pyk2. The binding of calmodulin to Pyk2 promotes the Pyk2 auto-phosphorylation at tyrosine 402. The phosphorylation of Pyk2 at Y402 provides docking site for the activation of Src kinase, which is able to further promote the assembly of invadopodia and remodeling of extracellular matrix. By regulating focal adhesion turnover and invadopodia formation, the hyperactive SOCE in cancer cells is able to promote cancer cell migration, invasion and metastasis.