Targeting calcium signaling in cancer therapy

Abstract

The intracellular calcium ions (Ca²⁺) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca²⁺ homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Ca²⁺ signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca²⁺ channels, transporters and Ca²⁺-ATPases, which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca²⁺ channels/transporters or Ca²⁺-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research into the understanding of cellular mechanisms underlying the regulation of Ca²⁺ signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca²⁺ channels or transporters.

Keywords: 20-GPPD, 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol; Apoptosis; CBD, cannabidiol; CBG, cannabigerol; CPZ, capsazepine; CRAC, Ca2+ release-activated Ca2+ channel; CTL, cytotoxic T cells; CYP3A4, cytochrome P450 3A4; Ca2+ channels; CaM, calmodulin; CaMKII, calmodulin-dependent protein kinase II; Cancer therapy; Cell proliferation; Channel blockers;; ER/SR, endoplasmic/sarcoplasmic reticulum; HCX, H+/Ca2+ exchangers; IP3, inositol 1,4,5-trisphosphate; IP3R (1, 2, 3), IP3 receptor (type 1, type 2, type 3); MCU, mitochondrial Ca2+ uniporter; MCUR1, MCU uniporter regulator 1; MICU (1, 2, 3), mitochondrial calcium uptake (type 1, type 2, type 3); MLCK, myosin light-chain kinase; Migration; NCX, Na+/Ca2+ exchanger; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; NSCLC, non-small cell lung cancer; OSCC, oral squamous cell carcinoma cells; PKC, protein kinase C; PM, plasma membrane; PMCA, plasma membrane Ca2+-ATPase; PTP, permeability transition pore; ROS, reactive oxygen species; RyR, ryanodine receptor; SERCA, SR/ER Ca2+-ATPase; SOCE, store-operated Ca2+ entry; SPCA, secretory pathway Ca2+-ATPase; Store-operated Ca2+ entry; TEA, tetraethylammonium; TG, thapsigargin; TPC2, two-pore channel 2; TRIM, 1-(2-(trifluoromethyl) phenyl) imidazole; TRP (A, C, M, ML, N, P, V), transient receptor potential (ankyrin, canonical, melastatin, mucolipin, no mechanoreceptor potential C, polycystic, vanilloid); VGCC, voltage-gated Ca2+ channel; mAb, monoclonal antibody.

Graphical abstract

Figure 1

Important Ca²⁺ channels/transporters/pumps in cancer cells. The dynamic of intracellular Ca²⁺ is governed by a series of proteins: (1) IP₃Rs mediating Ca²⁺ release from endoplasmic reticulum (ER); (2) Ca²⁺-ATPases pumping Ca²⁺ from cytosol to the ER or to extracellular space; (3) plasma membrane Ca²⁺ channels or transporters, such as VGCCs, TRPs, CRACs, NCXs and P2 receptors; (4) mitochondrial Ca²⁺ uniporter. The tightly regulated Ca²⁺ signals in the form of waves, spikes or oscillations can regulate a wide range of cellular events, including gene transcription, proliferation, migration and apoptosis. Targeting the dysregulated Ca²⁺ channels/transporters/pumps may provide a promising chemotherapy for cancer patients.