Evidence documents that increased intracellular calcium stores are associated with highly metastatic melanoma cells [28]. Calcium released from ER facilitates melanoma cell migration. Epac1 activated by cAMP induces calcium elevation from ER via the PLC/IP₃ receptor pathway and facilitates cell migration with the involvement of actin assembly, which is inhibited by mSIRK, a Gβγ-activating peptide, activating calcium influx from the extracellular space [29,30]. The expression of cGMP phosphodiesterase PDE5A is downregulated by oncogenic BRAF in BRAF^V600E mutated melanoma by the extracellular-signal-regulated kinase (ERK) pathway, which induces an increase in [Ca²⁺]i, stimulating melanoma cell invasion and short-term and long-term lung colonization [31]. Y-box binding protein 1 is an unfavorable prognostic marker secreted from melanoma depending on [Ca²⁺]i and ATP levels, the expression of which increases in primary and metastatic melanoma, compared to benign melanocytic nevi. Conversely, elevated Y-box binding protein 1 secretion stimulates melanoma cell migration, invasion, and tumorigenicity [32]. Paradoxically, increased [Ca²⁺]i was reported to decrease melanoma progression. Olfactory receptor 51E2 activated by its ligand β-ionone suppresses the migration of vertical-growth phase melanoma cells by increasing [Ca²+]i [33].

Since [Ca²⁺]i plays an important mechanistic role in melanoma progression, the role of calcium channels cannot be neglected. Basically, NMDAR calcium channel function is weak in melanoma cells but strongly contributes to cell proliferation and invasion when its encoding gene GRIN2A is mutated at certain sites, such as G762E, with less glutamate supplementation [34]. Another glutamate receptor calcium channel mGluR5 was proved to have a profound effect on melanoma progression in vivo by triggering the phosphorylation of ERK [5]. The ERK pathway is also implicated in SOCE-mediated melanoma progression. Inhibition of SOCE by knockdown of STIM1 or Orai or by SOCE inhibitors suppresses melanoma cell proliferation and migration, while induction of SOCE activates ERK, which is inhibited by calmodulin kinase II or Raf-1 inhibitors [35]. TPC2 influences melanoma progression via SOCE. Downregulation of TPC2 expression in metastatic melanoma leads to a decrease of Orai1 expression and an increase of YAP/TAZ activity, which is responsible for melanoma’s aggressive property [36]. In BRAF mutant melanoma—the BRAF^V600E mutation in particular—the expression of Ca²⁺-ATPase isoform 4b (PMCA4b) on the plasma membrane is low compared with benign nevi and is markedly elevated by vemurafenib (BRAF inhibitor) or selumetinib (MEK inhibitor) treatment, which indicates crosstalk between PMCA4b and the MAPK pathway. Activation of p38 MAPK induces the degradation of PMCA4b, while suppression of p38 MAPK by increasing the abundance of PMCA4b promotes the [Ca²⁺]i clearance and inhibits the migration of melanoma cells [37,38]. Moreover, SERCA on the ER membrane, controlled by the interaction between calcium-modulating cyclophilin ligand and basigin, was reported to have an effect on invasion and metastasis by regulating [Ca²⁺]i and matrix metalloproteinase (MMP)-9 activity in A375 cells [39]. Unlike Ca²⁺-ATPase, T-type VDCCs drive migration and invasion in BRAF mutant melanoma cells depending on Snail1 levels, suggesting therapeutic strategies by blocking T-type VDCCs to inhibit progression of melanoma [40]. Other ion channels are implicated in melanoma progression through calcium signaling. Nav1.6 sodium channel promotes melanoma cell (WM266 and WM115) invasion and proliferation by mTOR-mediated Na⁺/Ca2⁺ exchange [41]. KCa3.1 potassium channel was reported to promote melanoma cell migration by controlling the secretion of melanoma inhibitory activity proteins depending on [Ca²+]i [42].

Ca²⁺ signaling also leads to cell morphological and phenotypical changes, including the elongated cell axonal- and mesenchymal-like shape, formulation of invadopodia, and altered cytoskeleton structure, making cancer cells become more deformable and more invasive. Except for the role in melanogenesis, synaptotagmin-4 is thought to have a relationship with the growth and metastasis of melanoma by influencing axonal elongation [43]. Orai- and STIM1-mediated Ca²⁺ oscillation signals were reported to facilitate invadopodium assembly and thus promote melanoma invasion by regulating the recycling of membrane-bound MT1-MMP and extracellular matrix (ECM) remodeling [18,44]. The effect of the β2-adrenergic–Ca²⁺–actin axis on cancer invasion was reported in melanoma and other cancer types. β-adrenergic receptor (βAR) signaling triggers actin remodeling and reorganization to enhance cell contractility and promote cell invasion. β-adrenergic receptor-induced Ca²⁺ acts as a regulator of cytoskeletal actin by directly binding to actin or binding to filamin, the crosslinker of actin [45]. Meghnani et al. reported the upregulated expression of receptor for advanced glycation end products (RAGE) in melanoma patients in late metastatic stages. Overexpression of RAGE induced melanoma cells to become more metastatic by triggering cells into mesenchymal-like morphologies, which is associated with the upregulation of its ligand S100B, a calcium-binding protein [46].

Other factors (melanoma stem cells), other proteins (S100 family, E-cadherin, and calpain), and the Wnt/Ca²⁺ pathway influence melanoma progression through calcium signaling. Ca²⁺ released through IP₃R in melanoma cells is crucial for the function of cancer stem cells. IP₃R impairment leads to a diminution in the population of melanoma stem cells and reduced melanoma growth [47]. A network analysis of the expression of Ca²⁺ signaling and stem cell pluripotency-related genes (e.g., GSTP1, SMAD4, CTNNB1, MAPK3, GNAQ, PPP1CC, GSK3B, and PRKACA) showed some candidates that may contribute to the melanoma metastatic transformation and potential therapeutic biomarkers for metastatic melanoma [48].

S100A4 is a metastasis-promoting protein in melanoma cells which acts by targeting metabolic reprogramming, that is, the suppression of mitochondrial respiration and the activation of aerobic glycolysis [49]. Upregulation of S100P, ezrin, and RAGE improves the malignancy of melanoma [50]. E-cadherin has extracellular Ca²⁺-binding domains whose functions are dependent on Ca²⁺ and is essential for melanogenesis and melanoma suppression. E-cadherin silencing is related to melanoma metastatic dissemination and poor prognosis [51,52]. The decreasing expression of E-cadherin by overexpression of T-box transcription factors Tbx2 and Tbx3 is associated with enhanced melanoma invasiveness [53]. Promoter methylation by activating E-cadherin expression represents its therapeutic role in the treatment of melanoma [51]. Evidence in vitro and in vivo showed that inhibition of calpain, whose activity is promoted by calcium signaling, blunts melanoma growth, allows melanoma cells to escape from anti-tumor immunity, and increases metastatic dissemination by accelerating the migration process and reducing apoptosis [54].

Wnt5a was found to be expressed in highly aggressive melanoma and was able to increase melanoma invasive potential by activating PKC and raising [Ca²⁺]i in a transfected model [55]. Interestingly, Wnt5a signaling was engaged into melanoma cell movement, rendering them more aggressive. Wnt5a leads to the remodeling of the cytoskeleton and increases melanoma motility by activating calpain-1, leading to the cleavage of filamin A [56]. The assembly of the “Wnt-receptor-actin-myosin-polarity” structure, which is promoted by Wnt5a, promotes actomyosin contractility and substrate detachment for membrane retraction, mediated by the recruitment of cortical ER and elevation of Ca²⁺ [57]. (Figure 2).