Remodelling of Ca2+ transport in cancer: how it contributes to cancer hallmarks?

Abstract

Cancer involves defects in the mechanisms underlying cell proliferation, death and migration. Calcium ions are central to these phenomena, serving as major signalling agents with spatial localization, magnitude and temporal characteristics of calcium signals ultimately determining cell's fate. Cellular Ca(2+) signalling is determined by the concerted action of a molecular Ca(2+)-handling toolkit which includes: active energy-dependent Ca(2+) transporters, Ca(2+)-permeable ion channels, Ca(2+)-binding and storage proteins, Ca(2+)-dependent effectors. In cancer, because of mutations, aberrant expression, regulation and/or subcellular targeting of Ca(2+)-handling/transport protein(s) normal relationships among extracellular, cytosolic, endoplasmic reticulum and mitochondrial Ca(2+) concentrations or spatio-temporal patterns of Ca(2+) signalling become distorted. This causes deregulation of Ca(2+)-dependent effectors that control signalling pathways determining cell's behaviour in a way to promote pathophysiological cancer hallmarks such as enhanced proliferation, survival and invasion. Despite the progress in our understanding of Ca(2+) homeostasis remodelling in cancer cells as well as in identification of the key Ca(2+)-transport molecules promoting certain malignant phenotypes, there is still a lot of work to be done to transform fundamental findings and concepts into new Ca(2+) transport-targeting tools for cancer diagnosis and treatment.

Keywords: apoptosis; calcium signalling; cancer; metastasis; migration; proliferation.

Figure 1.

Ca²⁺ transport remodelling in promotion of cancer cell proliferation. Black arrows show the sequence of events; step-by-step following of black arrows enables a specific pathway to be traced; upward arrows in the boxes indicate increased expression and/or function of certain protein(s) or stimulation of a specified process. The boxes related to Ca²⁺ entry and Ca²⁺ release mechanisms are coloured in blue and green, respectively. See text for details. ER, endoplasmic reticulum; IP₃R, inositol trisphosphate receptor-channel; NFAT, nuclear factor of activated T cells; ORAI1 and ORAI3, channel-forming proteins of SOC; PLC, phospholipase C; SERCA, sarco(endo)plasmic reticulum calcium ATPase; SOC, store-operated channels; SPCA2, secretory pathway calcium ATPase 2; STIM1, stromal interaction molecule 1 (ER Ca²⁺ sensor in SOC activation); TRP, various members of transient receptor potential channel family; RYR, ryanodine receptor-channel; VGCC, voltage-gated calcium channels. (Online version in colour.)

Figure 2.

Ca²⁺ transport remodelling in conferring apoptosis resistance in cancer cells. Black arrows show the sequence of events; step-by-step following of black arrows enables a specific pathway to be traced; green upward arrows in the boxes indicate increased expression and/or function of certain protein(s) or stimulation of a specified process; orange downward arrows in the boxes indicate decreased expression and/or function of certain protein(s) or inhibition of a specified process. The boxes related to Ca²⁺ entry, Ca²⁺ release and Ca²⁺ extrusion mechanisms are coloured in blue, green and magenta, respectively. See text for details. Abbreviations in addition to those specified for figure 1. MPT, mitochondrial permeability transition; PMCA, plasma membrane calcium ATPase. (Online version in colour.)

Figure 3.

Ca²⁺ transport remodelling in the promotion of cancer cell metastasis. Black arrows show the sequence of events; step-by-step following of black arrows enables a specific pathway to be traced; green upward arrows in the boxes indicate increased expression and/or function of certain protein(s) or stimulation of a specified process. The boxes related to Ca²⁺ entry and Ca²⁺ release mechanisms are coloured in blue and green, respectively. See text for details. Abbreviations in addition to those specified for figures 1 and 2: ECM, extracellular matrix; SOCE, store-operated calcium entry. (Online version in colour.)

Figure 4.

Ca²⁺ transport remodelling in tumour vascularization. Black arrows show the sequence of events; step-by-step following of black arrows enables a specific pathway to be traced; green upward arrows in the boxes indicate increased expression and/or function of certain protein(s) or stimulation of a specified process. The boxes related to Ca²⁺ entry and Ca²⁺ release mechanisms are coloured in blue and green, respectively. See text for details. Abbreviations in addition to those specified for figures 1–3: ECs, vascular endothelial cells; VEGF, vascular endothelial growth factor. (Online version in colour.)