Plasma Membrane Ion Channels and Epithelial to Mesenchymal Transition in Cancer Cells
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2311 I Azimi and G R Monteith Ion channels and EMT 23:11 R517–R525 Review in cancer Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells Iman Azimi1,2,3 and Gregory R Monteith1,2,3 Correspondence should be addressed 1 The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia to G R Monteith 2 Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia Email 3 Translational Research Institute, Brisbane, Queensland, Australia [email protected] Abstract A variety of studies have suggested that epithelial to mesenchymal transition (EMT) Key Words may be important in the progression of cancer in patients through metastasis and/or f calcium therapeutic resistance. A number of pathways have been investigated in EMT in cancer f cell signalling cells. Recently, changes in plasma membrane ion channel expression as a consequence f intracellular signalling of EMT have been reported. Other studies have identified specific ion channels able to f metastasis regulate aspects of EMT induction. The utility of plasma membrane ion channels as targets for pharmacological modulation make them attractive for therapeutic approaches to target EMT. In this review, we provide an overview of some of the key plasma membrane ion channel types and highlight some of the studies that are beginning to define changes in plasma membrane ion channels as a consequence of EMT and also their possible roles in Endocrine-Related Cancer Endocrine-Related Cancer Endocrine-Related EMT induction. (2016) 23, R517–R525 Introduction Epithelial to mesenchymal transition (EMT) refers to the treatment of the primary tumour are often feasible process whereby epithelial cells which typically exhibit (e.g. breast and prostate). Metastasis is a highly regulated features such as strong cell to cell adhesion and apical- process whereby cells escape the primary tumour, enter basal polarity, lose these properties and acquire others such the circulatory system and deposit at a metastatic site as greater motility and a spindle like morphology (Thiery (Hanahan & Weinberg 2011). There is clear coordination et al. 2009, van Denderen & Thompson 2013) (Fig. 1). of processes in metastasis and this is reflected in the EMT is a key event in developmental processes including propensity of different cancer subtypes to preferentially embryogenesis where it is associated with implantation and form metastatic lesions in specific sites. The loss of cell- embryonic gastrulation (Kalluri & Weinberg 2009). EMT is to-cell adhesion, the acquisition of motility, the ability also a feature of other aspects of normal physiology such to degrade the surrounding extracellular matrix and to as wound healing where it has an important role in tissue survive stresses such as that induced by entry into the regeneration, and organ fibrosis Kalluri( & Weinberg 2009). circulation are all features that are required of cancer cells during metastasis. It is therefore not surprising that it is believed that as cells leave the primary tumour they may EMT in cancer undergo processes similar to EMT (Heerboth et al. 2015). Metastasis is the cause of mortality in cancer types that These include the expression of the specific transcription originate from organs where surgical resection and/or factors Snail and Twist, expression of mesenchymal http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-16-0334 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 10:32:49AM via free access 10.1530/ERC-16-0334 Review I Azimi and G R Monteith Ion channels and EMT 23:11 R518 in cancer Figure 1 Epithelial to mesenchymal transition (EMT). EMT is a reversible process whereby epithelial cells with polygonal morphology, apical–basal polarity, and high cell–cell/cell–ECM adhesion, and stationary position acquire mesenchymal features including spindle-like morphology, anterior– posterior polarity, cell–cell/cell–ECM dissociation and enhanced motility. EMT can be induced by microenvironmental factors including growth factors, cytokines and hypoxia. The reverse process of EMT is called mesenchymal to epithelial transition (MET). markers such as vimentin and N-cadherin, and loss of which is a consequence of EMT (Davis et al. 2014b). epithelial markers such as E-cadherin (Tsai & Yang 2013). One class of proteins that are the target of existing Indeed, the consequences of EMT have been reported as drugs and many drug development programs are ion increased motility and a remodelling of cellular adhesion channels. Plasmalemmal ion channels in particular are (Lamouille et al. 2014). EMT in cancer cells is also often amenable to pharmacological modulation due to associated with the acquisition of therapeutic resistance their extracellular domains. The availability of selective (Singh & Settleman 2010). Although some very recent inhibitors to specific ion channel isoforms also allows Endocrine-Related Cancer Endocrine-Related studies indicate that in some cancers EMT may be more chemogenomic and other methods to develop new important in the acquisition of therapeutic resistance therapeutics. than metastasis (Fischer et al. 2015, Zheng et al. 2015), understanding the induction of EMT and the properties of Ion channels as regulators of cellular the mesenchymal state would clearly help identify novel processes therapeutic targets. A number of factors in the tumour microenvironment The presence of ion gradients across the plasma have been identified as inducers of EMT in cancer cells. membrane is a defining feature of mammalian cells. The In breast cancer cells, growth factors such as epidermal sodium ion gradient is maintained by Na+/K+-ATPases that growth factor (EGF), and hypoxia have been shown actively pump Na+ ions from the cytoplasm to maintain to induce EMT in a variety of in vitro models, such as a lower intracellular free Na+ level compared to those MDA-MB-468 breast cancer cells and ZR-75-1 breast cancer of the extracellular space (Castillo et al. 2015). Changes cells (Lester et al. 2007, Davis et al. 2014a). In prostate in this gradient can lead to rapid changes in membrane cancer cells, EMT is induced by epidermal growth factor potential and drive action potentials in excitable cells. 2+ 2+ (EGF) (Zhang et al. 2013b) and Growth and differentiation Similarly, changes in cytosolic free Ca ([Ca ]CYT) levels factor 9 (GDF-9) (Bokobza et al. 2011). Studies in lung can be mediated by activation of Ca2+ permeable ion cancer cells have demonstrated that hypoxia induces EMT channels and such changes have important roles in an through protein kinase A (PKA) activity in a hypoxia- array of cellular processes including fertilization, muscle inducible factor 1-alpha (HIF1-α) dependent manner contraction, hormone secretion, gene transcription and (Shaikh et al. 2012). A variety of druggable targets have cell death (Berridge et al. 2003). The diversity of processes been identified as potential mechanisms to control EMT influenced by changes in Na+, Ca2+ and K+ and other induction and/or target the mesenchymal phenotype ions through the opening of ion channels, requires the http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-16-0334 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 10:32:49AM via free access Review I Azimi and G R Monteith Ion channels and EMT 23:11 R519 in cancer cell to selectively control such changes and the way such channels. Examination of each of these channel types changes are decoded to alter cellular processes. Hence, it provides insight into their diversity. These channels can is not surprising that there are a plethora of ion channels differ dramatically in their properties from ion selectivity in cells. For example there are over 20 genes that encode to their mechanism of activation. for just one specific class of ion channel – transient The diversity in ion channel properties is clear in the receptor potential (TRP) channels in humans. The next plasma membrane Ca2+ channels presented in Fig. 2 – section provides an outline of the general properties of Orai, TRP, P2X and voltage gated Ca2+ channels (VGCC). ion channels relevant to this review. We then provide a These classes have clear differences in their mechanism specific overview of studies that have identified roles of of activation. For example the Orai1 protein is part of a ion channels in EMT induction and/or remodelling. complex whereby Ca2+ influx is activated by the depletion of endoplasmic reticulum Ca2+ stores (Azimi et al. 2014). In contrast, TRP channels have been described as sensors, Plasma membrane ion channels as exemplified by TRPV1 a Ca2+ permeable ion channel There are a variety of ion channels with different activated by heat and the hot chilli component, capsaicin permeability and selectivity for cations or anions. A (Azimi et al. 2014). Other ligand gated calcium channels comprehensive review of all ion channels even just include ionotropic glutamate receptors and also P2X those of the plasma membrane is well beyond the scope channels that are activated by some nucleosides (e.g. ATP) of this review. Hence, readers are directed to sources of whereas VGCCs are activated by changes in membrane comprehensive lists and review of ion channels such as potential (Azimi et al. 2014). Even within classes of Ca2+ the IUPHAR/BPS guide to pharmacology (Southan et al. channels there is great diversity of activators (e.g. TRPV1 2016), which includes other channels not discussed is activated by capsaicin whereas TRPM8 is activated in this review such as acid-sensing (proton-gated) ion by menthol) and ion selectivity (e.g. TRPV6 is highly channels (ASICs) and some ligand gated Ca2+ channels selective for Ca2+ ions whereas TRPV1 is also permeable such as ionotropic glutamate receptors. Arguably, the most to Na+ ions) (Azimi et al. 2014). The remodelling of Ca2+ extensively studied plasma membrane ion channels are channel expression has been defined in some cancers those depicted in Fig.