Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer

Abstract

Progress through the cell mitotic cycle requires precise timing of the intrinsic molecular steps and tight coordination with the environmental signals that maintain a cell into the proper physiological context. Because of their great functional flexibility, ion channels coordinate the upstream and downstream signals that converge on the cell cycle machinery. Both voltage- and ligand-gated channels have been implicated in the control of different cell cycle checkpoints in normal as well as neoplastic cells. Ion channels mediate the calcium signals that punctuate the mitotic process, the cell volume oscillations typical of cycling cells, and the exocytosis of autocrine or angiogenetic factors. Other functions of ion channels in proliferation are still matter of debate. These may or may not depend on ion transport, as the channel proteins can form macromolecular complexes with growth factor and cell adhesion receptors. Direct conformational coupling with the cytoplasmic regulatory proteins is also possible. Derangement or relaxed control of the above processes can promote neoplasia. Specific types of ion channels have turned out to participate in the different stages of the tumor progression, in which cell heterogeneity is increased by the selection of malignant cell clones expressing the ion channel types that better support unrestrained growth. However, a comprehensive mechanistic picture of the functional relations between ion channels and cell proliferation is yet not available, partly because of the considerable experimental challenges offered by studying these processes in living mammalian cells. No doubt, such studies will constitute one of the most fruitful research fields for the next generation of cell physiologists.

Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium

“…This is the reason why the role of ionic channels in the control of the cell cycle in normal and transformed cells has already been addressed by many research groups, in the attempt of identifying efficient targets for therapeutic approaches (Abdul et al, 2003;Arcangeli et al, 2009;Asher et al, 2010;Aydar et al, 2009;Becchetti, 2011;Currò, 2014;Wang, 2004). The detailed electrophysiological analysis performed in this study on MCF-7 cells adds new insights to the elucidation of the possible mechanisms involved in the oncostatic action of melatonin based on the cultured condition.…”

“…However, to elucidate this issue, it must be considered that besides the voltage dependent ion channel activation, many other mechanisms may contribute to the establishment of resting membrane potential, such as stretch activated channels (Aydar et al, 2009;Formigli et al, 2007;Sbrana et al, 2008), ionic pumps (2Na/3 K ATPase and Ca 2 þ pump), 3Na/Ca exchanger (Becchetti 2011) and voltage-independent channels as IKCa and K ATP (Abdul et al, 2003;Blackiston et al, 2009;Haren et al, 2010;Klimatcheva and Wonderlin, 1999), and that the complexity of the scenario requires further investigations.…”

“…Resting membrane potential is typically more depolarized in undifferentiated respect to differentiated cells (O'Grady and Lee, 2005;Pardo, 2004) and in cancer cells respect to terminally differentiated cells (Kunzelmann, 2005). Of interest, resting membrane potential and the type and amount of K þ and Ca 2 þ currents change during both cell cycle and differentiation (Blackiston et al, 2009;Sundelacruz et al, 2009) and are atypically modified in cancer cells (Becchetti, 2011;Bielanska et al, 2009;Haren et al, 2010;Lang et al, 2003;Ohkubo and Yamazaki, 2012;Ouadid-Ahidouch and Ahidouch, 2008).…”

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

“…In fact, variations in cellular concentrations of certain ions coordinate the signals that converge on cell cycle checkpoints [2], regulating the proliferative capacity of cells and their differentiation. Similarly, the triggering of the apoptotic programmed cell death also depends on ion fluxes mediated by cellular ion channels [3].…”

Functional properties of ion channels and transporters in tumour vascularization

“…On the other hand, the role of VOCs in tumour progression has been largely described and different data point to Na þ , K þ and Ca 2þ channels as key players, suitable to be specifically potential target in clinical treatments [23]. K þ channels (K V ) attracted most of the work in oncology since the early discovery unveiling their role in the control of cell proliferation [24,25].…”