Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?

Abstract

Genomic instability is a primary cause and fundamental feature of human cancer. However, all cancer cell genotypes generally translate into several common pathophysiological features, often referred to as cancer hallmarks. Although nowadays the catalog of cancer hallmarks is quite broad, the most common and obvious of them are 1) uncontrolled proliferation, 2) resistance to programmed cell death (apoptosis), 3) tissue invasion and metastasis, and 4) sustained angiogenesis. Among the genes affected by cancer, those encoding ion channels are present. Membrane proteins responsible for signaling within cell and among cells, for coupling of extracellular events with intracellular responses, and for maintaining intracellular ionic homeostasis ion channels contribute to various extents to pathophysiological features of each cancer hallmark. Moreover, tight association of these hallmarks with ion channel dysfunction gives a good reason to classify them as special type of channelopathies, namely oncochannelopathies. Although the relation of cancer hallmarks to ion channel dysfunction differs from classical definition of channelopathies, as disease states causally linked with inherited mutations of ion channel genes that alter channel's biophysical properties, in a broader context of the disease state, to which pathogenesis ion channels essentially contribute, such classification seems absolutely appropriate. In this review the authors provide arguments to substantiate such point of view.

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

“…The IGF2 gene and IRS2 gene are frequently gained in colon cancer (Cancer Genome Atlas, 2012) and have been proposed as a colorectal cancer "driver" oncogenes (Day et al, 2013). TRPV6 gene is frequently up regulated in prostate, colon, and other cancer tissues (V. Lehen'kyi, Raphael, & Prevarskaya, 2012;Prevarskaya, Skryma, & Shuba, 2018). At present, it is unclear whether the elevated TRPV6 expression promotes tumor growth or it is an adaptive response (V. Lehen'kyi et al, 2012;Prevarskaya et al, 2018).…”

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel KCa3.1

“…Fort he development of small-molecule fluorescently labeled probes of the K Ca 3.1 channel, senicapoc (1)s erved as starting point. Senicapoc (1)has ahigh affinity towards the K Ca 3.1 channel in the low-nanomolar range (IC 50 = 11 AE 2nm ; measured on human erythrocytes) and excellent selectivity over related ion channels. [10] In order to introduce af luorescent dye one F-atom of senicapoc should be replaced by ahydroxy moiety.The OH moiety of the senicapoc derivative 2 should allow broad chemical modifications including the introduction of afluorescent dye ( Figure 1).…”

“…Ion channels play ac ritical role in the progression of cancer and contribute to features of essentially all "cancer hallmarks". [1] Thec alcium-activated potassium channel 3.1 (K Ca 3.1) is an intensively studied ion channel in this context. It is involved in critical steps of the metastatic cascade,s uch as proliferation, migration, invasion, and extravasation.…”

Voltage-dependent activation of Rac1 by Nav1.5 channels promotes cell migration

“…Another set of proteins that play a key role in regulating cellular migration is ion channels (Schwab, Fabian, Hanley, & Stock, 2012). Changes in ion channel expression and/or activity in cancer cells regulate the plasma membrane potential (Vm) and intracellular signaling cascades as a result of altered ion flux (Brackenbury, 2016;Prevarskaya, Skryma, & Shuba, 2018). Motile cancer cells possess a more depolarized Vm compared to terminallydifferentiated non-cancer cells (Yang & Brackenbury, 2013).…”