Ion Channels: A New Cancer Hallmark

Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca2+ permeable channels, K+ channels, Na+ channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca2+ permeable channels, K+ channels, Na+ channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors.

 

1. INTRODUCTION

Ion transport across the cell membrane plays a crucial role in fundamental tumour cell functions [1–3], such as cell volume regulation [4,5], migration [5], cell cycle progression [5,6], cell proliferation [5,6] as well as cell death [4,5]. All those functions are critically important for tumour cell survival and metastasis [1]. Moreover, ion channels participate in the regulation of other cell functions again relevant for migration [7], and thus metastasis. Ion transport across the membrane of non-tumour cells may further be decisive for tumour cell survival. For instance, ion channels participate in the regulation of tumour vascularization [8] and ion channels are important for the proliferation and response of immune cells attacking tumour cells [9].

Tumour-relevant ion channels are upregulated by growth factors and hormones [10] to the extent that a given ion channel is critically important for the survival of a tumour cell, this ion channel may be considered a target for the treatment of the respective tumour [11]. Needless to say, however, that only those channels are clinically applicable for the suppression of tumour growth, which do not serve critically important functions in other cells, for example channels required for cardiac repolarization. Moreover, ion channels may be relevant for the proliferation and survival of cells other than tumour cells.

This short synopsis discusses the significance of Ca2+ channels, K+ channels, Na+ channels and Cl− channels in the cell membrane. For the involvement of other channels or transporters, such as mitochondrial channels [12], cell membrane water channels [13], Na+/H+ exchanger [14,15], Na+,K+,2Cl− cotransporters [16–19], KCl cotransporters [20], Na+,K+-ATPase [4,21–33], MDR [34], as well as several H+ transporters, such as vacuolar H+-ATPases, H+/Cl− symporters, monocarboxylate transporters, or Na+-dependent Cl−/HCO3- exchangers (for reviews, see [35–38]) in cell proliferation, cell death, tumour growth and migration, the reader is referred to the respective reviews or original papers. Moreover, the reader is encouraged to read the other contributions of this special issue on this exciting topic. In this review, the case is made that ion channels and transporters are indeed critically important for tumour growth and metastasis and are thus potential targets in the treatment of malignancy.

 

Conclusions

Increasing evidence suggests that ion channels and pumps are involved in the regulation of cell proliferation and migration, and channel proteins have been shown to form macromolecular complexes with cell adhesion molecules and other signaling proteins. As these roles of ion channels and pumps are further elucidated, it is being increasingly suggested that regulation of ion channels and pumps could contribute to cancer progression. Here we discussed that aberrant expression and function of several types of ion channels and pumps have been found in multiple cancers including brain cancer, and in particular, glioblastoma. Knowing that these proteins are involved in multiple malignant characteristics of multiple cancers, ion channels and pumps could be potential targets for therapy.

 

REFERENCES

1. Djamgoz MB, Onkal R. 2013. Persistent current blockers of voltage-gated sodium channels: a clinical opportunity for controlling metastatic disease. Recent Patents Anticancer Drug Discov. 8, 66–84 [PubMed]

2. Arcangeli A, Becchetti A. 2006. Complex functional interaction between integrin receptors and ion channels. Trends Cell Biol. 16, 631–639 (doi:10.1016/j.tcb.2006.10.003) [PubMed]

3. Huber SM. 2013. Oncochannels. Cell Calcium 53, 241–255 (doi:10.1016/j.ceca.2013.01.001) [PubMed]

4. Lang F, Hoffmann EK. 2012. Role of ion transport in control of apoptotic cell death. Compr. Physiol. 2m 2037–2061 [PubMed]

5. Turner KL, Sontheimer H. 2014. Cl− and K+ channels and their role in primary brain tumour biology. Phil. Trans. R. Soc. B 369, 20130095 (doi:10.1098/rstb.2013.0095) [PMC free article] [PubMed]

6. Becchetti A. 2011. Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer. Am. J. Physiol. Cell Physiol. 301, C255–C265 (doi:10.1152/ajpcell.00047.2011) [PubMed]

7. Kessler D, Gruen GC, Heider D, Morgner J, Reis H, Schmid KW, Jendrossek V. 2012. The action of small GTPases Rab11 and Rab25 in vesicle trafficking during cell migration. Cell Physiol. Biochem. 29, 647–656 (doi:10.1159/000295249) [PubMed]

8. Fiorio Pla A, Munaron L. 2014. Functional properties of ion channels and transporters in tumour vascularization. Phil. Trans. R. Soc. B 369, 20130103 (doi:10.1098/rstb.2013.0103) [PMC free article] [PubMed]

9. Panyi G, Beeton C, Felipe A. 2014. Ion channels and anti-cancer immunity. Phil. Trans. R. Soc. B 369, 20130106 (doi:10.1098/rstb.2013.0106) [PMC free article] [PubMed]

10. Fraser SP, Ozerlat-Gunduz I, Brackenbury WJ, Fitzgerald EM, Campbell TM, Coombes RC, Djamgoz MBA. 2014. Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation. Phil. Trans. R. Soc. B 369, 20130105 (doi:10.1098/rstb.2013.0105) [PMC free article] [PubMed]

11. Oosterwijk E, Gillies RJ. 2014. Targeting ion transport in cancer. Phil. Trans. R. Soc. B 369, 20130107 (doi:10.1098/rstb.2013.0107) [PMC free article] [PubMed]

12. Leanza L, Biasutto L, Manago A, Gulbins E, Zoratti M, Szabo I. 2013. Intracellular ion channels and cancer. Front. Physiol. 4, 227 (doi:10.3389/fphys.2013.00227) [PMC free article] [PubMed]

13. Tie L, Lu N, Pan XY, Pan Y, An Y, Gao JW, Lin YH, Yu HM, Li XJ. 2012. Hypoxia-induced up-regulation of aquaporin-1 protein in prostate cancer cells in a p38-dependent manner. Cell Physiol. Biochem. 29, 269–280 (doi:10.1159/000337608) [PubMed]

14. Reshkin SJ, Greco MR, Cardone RA. 2014. Role of pHi, and proton transporters in oncogene-driven neoplastic transformation. Phil. Trans. R. Soc. B 369, 20130100 (doi:10.1098/rstb.2013.0100) [PMC free article] [PubMed]

15. Andersen AP, Moreira JMA, Pedersen SF. 2014. Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment. Phil. Trans. R. Soc. B 369, 20130098 (doi:10.1098/rstb.2013.0098) [PMC free article] [PubMed]

16. Maeno E, Shimizu T, Okada Y. 2006. Normotonic cell shrinkage induces apoptosis under extracellular low Cl conditions in human lymphoid and epithelial cells. Acta Physiol. 187, 217–222 (doi:10.1111/j.1748-1716.2006.01554.x) [PubMed]

17. Maeno E, Takahashi N, Okada Y. 2006. Dysfunction of regulatory volume increase is a key component of apoptosis. FEBS Lett. 580, 6513–6517 (doi:10.1016/j.febslet.2006.10.074) [PubMed]

18. Nukui M, Shimizu T, Okada Y. 2006. Normotonic cell shrinkage induced by Na+ deprivation results in apoptotic cell death in human epithelial HeLa cells. J. Physiol. Sci. 56, 335–339 (doi:10.2170/physiolsci.RP009606) [PubMed]

19. Marklund L, Henriksson R, Grankvist K. 2001. Cisplatin-induced apoptosis of mesothelioma cells is affected by potassium ion flux modulator amphotericin B and bumetanide. Int. J. Cancer 93, 577–583 (doi:10.1002/ijc.1363) [PubMed]

20. Gagnon KB. 2012. High-grade glioma motility reduced by genetic knockdown of KCC3. Cell Physiol. Biochem. 30, 466–476 (doi:10.1159/000339040) [PubMed]

21. Bortner CD, Gomez-Angelats M, Cidlowski JA. 2001. Plasma membrane depolarization without repolarization is an early molecular event in anti-Fas-induced apoptosis. J. Biol. Chem. 276, 4304–4314 (doi:10.1074/jbc.M005171200) [PubMed]

22. Chueh SC, Guh JH, Chen J, Lai MK, Teng CM. 2001. Dual effects of ouabain on the regulation of proliferation and apoptosis in human prostatic smooth muscle cells. J. Urol. 166, 347–353 (doi:10.1016/S0022-5347(05)66157-5) [PubMed]

23. Esteves MB, Marques-Santos LF, Affonso-Mitidieri OR, Rumjanek VM. 2005. Ouabain exacerbates activation-induced cell death in human peripheral blood lymphocytes. An. Acad. Bras. Cienc. 77, 281–292 (doi:10.1590/S0001-37652005000200008) [PubMed]

24. Lang H, Schulte BA, Schmiedt RA. 2005. Ouabain induces apoptotic cell death in type I spiral ganglion neurons, but not type II neurons. J. Assoc. Res. Otolaryngol. 6, 63–74 (doi:10.1007/s10162-004-5021-6) [PMC free article] [PubMed]

25. McConkey DJ, Lin Y, Nutt LK, Ozel HZ, Newman RA. 2000. Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res. 60, 3807–3812 [PubMed]

26. Nobel CSI, Aronson JK, van den Dobbelsteen DJ, Slater AFG. 2000. Inhibition of Na+/K+-ATPase may be one mechanism contributing to potassium efflux and cell shrinkage in CD95-induced apoptosis. Apoptosis 5, 153–163 (doi:10.1023/A:1009684713784) [PubMed]

27. Olej B, dos Santos NF, Leal L, Rumjanek VM. 1998. Ouabain induces apoptosis on PHA-activated lymphocytes. Biosci. Rep. 18, 1–7 (doi:10.1023/A:1022259832207) [PubMed]

28. Xiao AY, Wei L, Xia S, Rothman S, Yu SP. 2002. Ionic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured cortical neurons. J. Neurosci. 22, 1350–1362 [PubMed]

29. Yu SP. 2003. Na+, K+-ATPase: the new face of an old player in pathogenesis and apoptotic/hybrid cell death. Biochem. Pharmacol. 66, 1601–1609 (doi:10.1016/S0006-2952(03)00531-8) [PubMed]

30. Sen N, Das BB, Ganguly A, Mukherjee T, Bandyopadhyay S, Majumder HK. 2004. Camptothecin-induced imbalance in intracellular cation homeostasis regulates programmed cell death in unicellular hemoflagellate Leishmania donovani. J. Biol. Chem. 279, 52 366–52 375 (doi:10.1074/jbc.M406705200) [PubMed]

31. Wang XQ, Xiao AY, Sheline C, Hyrc K, Yang A, Goldberg MP, Choi DW, Yu SP. 2003. Apoptotic insults impair Na+, K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress. J. Cell Sci. 116, 2099–2110 (doi:10.1242/jcs.00420) [PubMed]

32. Wang XQ, Xiao AY, Yang A, Larose L, Wei L, Yu SP. 2003. Block of Na+,K+-ATPase and induction of hybrid death by 4-aminopyridine in cultured cortical neurons. J. Pharmacol. Exp. Ther. 305, 502–506 (doi:10.1124/jpet.102.045013) [PubMed]

33. Panayiotidis MI, Bortner CD, Cidlowski JA. 2006. On the mechanism of ionic regulation of apoptosis: would the Na+/K+-ATPase please stand up? Acta Physiol. 187, 205–215 (doi:10.1111/j.1748-1716.2006.01562.x) [PubMed]

34. Hoffmann EK, Lambert IH. 2014. Ion channels and transporters in the development of drug resistance in cancer cells. Phil. Trans. R. Soc. B 369, 20130109 (doi:10.1098/rstb.2013.0109) [PMC free article] [PubMed]

35. Harguindey S, Arranz JL, Wahl ML, Orive G, Reshkin SJ. 2009. Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res. 29, 2127–2136 [PubMed]

36. Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ. 2005. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin—one single nature. Biochim. Biophys. Acta 1756, 1–24 (doi:10.1016/j.bbcan.2005.06.004) [PubMed]

37. Cardone RA, Casavola V, Reshkin SJ. 2005. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat. Rev. Cancer 5, 786–795 (doi:10.1038/nrc1713) [PubMed]

38. Parks SK, Chiche J, Pouyssegur J. 2011. pH control mechanisms of tumor survival and growth. J. Cell Physiol. 226, 299–308 (doi:10.1002/jcp.22400) [PubMed]

 

 

Ion channels – some basics

Every cell in the human body has a membrane potential associated with ion channels. Even red blood cells that do not have nuclei still possess these. The membrane potential is equivalent to some 10 million volts per metre and represents a huge force that could impact upon every protein in the cell membrane. When a typical voltage-gated ion (e.g. sodium) channel opens, ions permeate at an incredible rate of some 10,000 in a millisecond. These are extremely well-designed, cellular characteristics that, until recently, have been overlooked in cancer.

Many channels are expressed in cancers

Cancer cells have plasma membranes that exhibit electrochemical properties that are markedly different from normal cells. The membrane potential and ion channels play a range of key roles in cellular activities integral to the cancer process, from early gene expression to whole-cell behaviours like secretion and motility. The membrane voltage is a driving force even for the fundamental RAS-RAF-MAPK signalling cascade which is responsible for a number of cell behaviours associated with cancer, including growth, malignant transformation and drug resistance. Human lung adenocarcinoma stem cells downregulate their stemness and differentiate when their membrane potential is hyperpolarized. Furthermore, ion channel expression occurs early and is regulated by hormones and growth factors, well-known to be mainstream cancer mechanisms. It may not be surprising, therefore, that all major types and subtypes of ion channels are expressed in cancer cells. These include voltage-gated potassium, sodium, calcium and chloride channels, “transient receptor potential” (Trp) channels, and some ligand-gated ion channels.

Metastasis, the biggest problem in cancer

As far as ion channels are concerned, cancer is like the nervous system— all the channels are there, depending on the type and the stage of the cancer. So, the question is: Which ion channel would be best to target for controlling cancer? Inherent to this question is the crucial need to ensure that the ion channel(s) in question is sufficiently cancer-specific.

We have asked the question: Which ion channel is key to metastasis? This is the process by which cancer cells escape from the tumour, somehow enter the circulation and spread to distant organs. Metastatic disease is the main cause of death from cancer. There are significant differences between cancer cells of strong versus weak metastatic ability. Amongst these is de novo expression of voltage-gated sodium channels (VGSCs). Inhibiting VGSC expression/activity suppresses cancer cell invasiveness in vitro and metastasis in vivo. Importantly, the VGSC in some cancers is expressed as a neonatal splice variant, in line with the dedifferentiated nature of cancer. In breast and colon cancer, the neonatal VGSC (Nav1.5) differ from their adult counterpart by several extracellular amino acids around the gating region. Thus, the neonatal channel can be targeted (and blocked) selectively using small-molecule pharmacological agents or an antibody. Independently of this, the VGSC develops a ‘persistent current’ under hypoxic conditions well known to occur in growing tumours. There is evidence that it is mainly this current that underlies the metastasis-promoting role of the VGSC. Fortunately, also, the persistent current can be blocked using selective drugs whilst allowing nerve and muscle including cardiac functioning, dependent on the transient component of the VGSC current, to continue normally.

The challenges and the future

A number of challenges remain in exploiting ion channels in cancer. The main challenge is how to target cancer ion channels without affecting those in other tissues. Here, VGSCs tick all the boxes. The fact that the VGSC is neonatal with a pharmacology distinct from the normal adult counterpart elsewhere in the body is a distinct advantage. Another advantage is provided by the persistent current which is significant only under the pathologic hypoxic conditions of growing tumours. These are manageable challenges and add to the many advantages provided by ion channels, especially their expression early in cancer. Clearly, therefore, ion channels, in particular neonatal VGSCs, can be the next breakthrough in cancer. Already, there are many channel drugs to test against cancer and more will be developed. These will be non-toxic and free from the kinds of side effects associated with the current treatment modalities, so it should be possible to use them long-term. Thus, once we control metastasis, we could live with cancer, gain time to get rid of the primary tumour as well, and be cancer-free!

Ion channel: A protein that acts as a pore in a cell membrane and permits the selective passage of ions (such as potassium ions, sodium ions, and calcium ions), by means of which electrical current passes in and out of the cell. Ion channels also serve many other critically important functions including chemical signalling, transcellular transport, regulation of pH, and regulation of cell volume. Malfunction of ion channels can cause diseases in many tissues. The array of human diseases associated with defects in ion channels is growing. These diseases are called channelopathies.

The 2003 Nobel Prize in Chemistry was awarded jointly to Peter Agre and Roderick MacKinnon for their studies of the “tiny transportation tunnels” in cell walls. Dr. Agre, at Johns Hopkins University in Baltimore, discovered in 1988 the channels that let water pass in and out of cells while Dr. MacKinnon, at the Rockefeller University in New York, described in 1998 the first detailed structure of an ion channel.

Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?

ArticleinPhysiological Reviews 98(2):559-621 · April 2018 with 178

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.

Cancer stem cells (CSCs) are immortal cells in tumor tissues that have been proposed as the driving force of tumorigenesis and tumor invasion. Previously, ion channels were revealed to contribute to cancer cell proliferation, migration and apoptosis. Recent studies have demonstrated that ion channels are present in various CSCs; however, the functions of ion channels and their mechanisms in CSCs remain unknown. The present review aimed to focus on the roles of ion channels in the regulation of CSC behavior and the CSC-like properties of cancer cells. Evaluation of the relationship between ion channels and CSCs is critically important for understanding malignancy.

 

 

 

 

Cancer is a group of diseases that claim about 8.4 million lives every year (www.cancer.org). Although in the past decades, medical research has dramatically improved prevention, diagnosis, and treatment of cancer and despite being among the most preventable diseases, cancer remains a leading cause of death worldwide. 

Virtually, cancer can develop in any tissue and although each cancer type can be characterized by its unique features, the basic mechanisms that generate cancers are similar in all forms of the diseases. In a normal and healthy tissue, cell proliferation and cell death are controlled by a very complex, timely, and integrated signaling network that includes a series of checkpoints to ensure proper division factors of the cell or death. Cancer originates from an uncontrolled proliferation of cells that evade cell death and can eventually invade and/or outspread into other body compartments (metastasis). 

Cancer can be caused by a multitude of environmental factors that can be external such as smoking, sun exposure, and/or internal such as inherited faulty genes and/or infections. 

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Ion Channels in Aging and Aging-Related Diseases 43 http://dx.doi.org/10.5772/63951 

Although there can be a significant difference in the prevalence of cancers among different societies, overall cancer can affect every human being. Accordingly, aging is the highest single risk factor for developing cancer [66]. Recently, several ion channels have been found to play a major role in maintaining homeostasis of nonexcitable cells (Figure 1). 

Figure 1. Schematic representation of the contribution of different ion channels to the membrane potential in function of time (e.g., nonexcitable cell vs. neuronal action potential). Overexpression and/or upregulation (e.g., via hormone- dependent regulation) of certain ion channels can contribute to suppress differentiation and increase duplication rate resulting in the generation of a cancerogenic phenotype. 

In addition to the traditional role of allowing movements of ions across membranes, ion channels can also control mechanisms of transport, secretion, cell volume, and protein synthesis. For example, glucose transport is controlled by gradients of Na+ [67, 68]. Furthermore, several transcription factors or proteins involved in secretory mechanism are activated by Ca2+ [69, 70]. Therefore, changes of intracellular ionic concentrations can regulate a variety of cellular event ranging from production of energy to protein synthesis, which are necessary for the ultimate process of cellular duplication. Several studies have reported that cancer cells of different histogenesis can express specific ion channels that can play an important role during proliferation [71]. 

One of the better characterized ion channels in cancer is the Kv11.1 (hERG1) potassium channel. This potassium channel is encoded by the human ether-a-go-go related gene 1 (hERG1), which has been found typically expressed in the mammalian heart in which it play a fundamental role in controlling repolarization and duration of action potential [72]. Re‐ markably, hERG1 channel has also been found expressed in different nonexcitable cancer cells but not in the organ from which the tumor has originated [73]. This suggests that the presence of this channel might provide a selective advantage to proliferation. Blockade or stimulation of hERG1 channel activity determined a strong inhibitory effect on cancer cell proliferation [74–78]. In addition, complete removal of the hERG1 protein from breast cancer cells deter‐ mined death by activation of apoptosis [78]. These events indicate that the hERG1 is very important for cancer biology and its activity is kept under strict control. 

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44 Molecular Mechanisms of the Aging Process and Rejuvenation 

Interestingly, the inhibitory effect on cell proliferation as a consequence of chronic stimulation of hERG1 channel was characterized by activation of a “cellular senescent program” [76, 79]. Senescent cells were initially described by Hayflick and Moorhead [80] as cells that have lost the ability to duplicate, though they may not die. Today, cellular senescence is defined as a permanent arrest of the cell cycle induced by a progressive increase of stresses [81–83]. At this time, it is not known what kind of stresses hERG1 agonists produce on cancer cells but their effect is mediated by permanent arrest of the cell cycle, increased expression of tumor suppressors (e.g., p21waf/cif and p16INK4A) and decreased level of tumor markers (e.g., cyclins) resulting in a potent inhibition of cell proliferation [84–86]. This suggests that, by taking advantage of the ability to accelerate aging in cancer cells, hERG1 agonists could be used as an anticancer therapeutic strategy. 

Other ion channels have been found playing fundamental roles in regulating biochemical signaling that underline important events in cancer biology which includes metastasis. Overtime, cancer cells acquire the ability to move and invade surrounding tissues by protrud‐ ing membrane structures (invadopodia and pseudopodia) [87] through the intracellular space of the host organ. Remarkably, it has been discovered that ion channels are fundamental factors for regulation of invasion and migration of cancer cells. For example, the concerted activity of Ca2+, K+, and Cl channels that can exquisitely colocalize on the glioma surface membrane generates fluxes of ions and water that creates shrinkage of the membrane with consequent formation of invadopodia [88]. A direct consequence of this event is that cancer cells can move across tissue barriers (e.g., blood vessel) and colonize other body compartments. In addition, it has been shown that overexpression of Kv10 channels in which ion flux has been obstructed by a specific mutation did not lose the ability to promote cell proliferation [89, 90]. Although the mechanism through which this event occurs is not clearly understood, it appears that these channels can regulate activities of proteins that control proliferative cell signaling also when ion fluxes are not involved. 

As hormones control most of the major organ functions by activating a variety of cellular signaling, it is not surprising that ion channels can be downstream effectors of hormone receptors. Growth of many cancers can depend on altered expression of hormone receptors. For example, high percentage of breast cancers are very sensitive to the action of insulin and/ or sex hormones such as estrogen [91] or prostate cancer to testosterone [92]. Hormones can control ion channel activity by increasing their synthesis or by activating membrane signaling pathways (Figure 1). For example, hormones that bind G protein-coupled receptors (GPCR) produce release of the active βγsubunit of the heteromeric GTPase complex that ultimately binds and activates K+ channels (e.g., GIRK). Alternatively, soluble hormone receptors can activate nongenomic signaling resulting in stimulation of kinases or phosphatases that modulate activity of ion channels by directly targeting these proteins [93–95]. Furthermore, as secretion is vastly controlled by intracellular changes in Ca2+ concentrations (e.g., Ca2+- dependent insulin secretion), hormones must rely on ion channel function to be released in the body environment [96]. It is well established that with aging, organs become less sensitive to hormones. Although several examples of hormone-regulated ion channel activities have been proposed, knowledge on the role of these signalings in pathological conditions such as 

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Ion Channels in Aging and Aging-Related Diseases 45 http://dx.doi.org/10.5772/63951 

cancer, age-related disease, and/or aging is very limited. Therefore, it appears that there is a compelling need to study the role of hormonal regulation of ion channels to better understand both aging and cancer. 

6. Modulation of ion channels 

Another level of complexity of regulation of ion channels is added by a number of modulatory proteins that have been shown to bind channels and alter their biophysical properties. 

Figure 2. Presenilins differentially regulate RyR-mediated Ca2+ release.Representations of an individual RyR and its in‐ teraction with presenilin are shown in the top panels. Corresponding graphs below illustrate characteristics of Ca2+ transients mediated by RyR activity. Whole-cell cytosolic calcium concentrations (ordinate) are plotted over time (ab‐ scissa) to show the changes in the kinetics of Ca2+ transients dependent on presenilin binding to the RyR. Seesaws de‐ pict a predominant effect of presenilin 1 (PS1) over presenilin 2 PS2 or PS2 over PS1, as seen in young and aged animals, respectively [48]. (A) Binding of the PS1 N-terminal fragment to RyR increases open probability and results in heightened calcium release and fast channel inhibition by calcium at the RyR’s inhibitory low affinity Ca2+ binding site. (B) Binding of PS2 to the RyR blocks inhibition at the low affinity Ca2+ binding site resulting in an increased duration of the Ca2+ transient.This figure was modified from reference [103], which was published under Open Access licence (®2015 by Andrew J. Payne et al.). 

One of the best examples of involvement of ion channel modulation in aging includes Homer/ Vesl proteins and the group of presenilins. The group of Homer proteins (reviewed in [97]) is a family of ubiquitously expressed scaffolding molecules. Through a conserved binding motif, Homer proteins interact with a number of synaptic proteins. Homer 1 proteins directly interact with IP3Rs, RyRs, the group of transient receptor potential canonical (TRPC) channels, as well as mGluRs and some voltage-gated Ca2+ channels (reviewed in [97]). Intriguingly, in addition 

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46 Molecular Mechanisms of the Aging Process and Rejuvenation 

to enhancing synaptic transmission and providing a means of regulating excitability through tethering plasma membrane proteins to receptors and channels in the ER by formation of Homer tetramers, Homer proteins can alter the biophysical properties of their binding partners [98–100]. These interactions, especially with intracellular Ca2+ channels, have recently attracted increased interest due to their alterations in age-related diseases in the nervous system. For instance, in the aging brain, loss of the short isoform, Homer 1a, correlated with the loss of cognitive and motor function in mice [46]. Similarly, upregulation of the long isoform, Homer 1c, in the retina of glaucomatous mice showed a statistically significant association with severity of the disease phenotype and disease progression [47]. Furthermore, loss of Homer 1c immunoreactivity at glutamatergic synapses after experimental stroke was identified as a potential biomarker for early neurodegenerative processes, prior to initiation of apoptotic pathways [101]. Similarly, binding of presenilin proteins to RyRs results in a functional change of intracellular Ca2+ release [102–105]. Recent studies have demonstrated that altered levels of presenilin proteins in the aging brain correlate with the presence and severity of impairments in cognitive and motor function [48]; Figure 2), identifying the group of presenilins as putative drug target for neurodegeneration. In summary, intracellular Ca2+ channels are critical mediators of intracellular Ca2+ homeostasis and respond differentially to aging and patholog‐ ical stimuli including oxidative stress. Furthermore, intracellular Ca2+ signaling is differentially regulated in various cell types and tissues and by a large number of modulators, providing a multitude of targets for pharmaceutical intervention in conditions characterized by neurode‐ generation and aging. 

7. Perspective 

Aging is a process common to all living organisms that is associated with a progressive failure to adapt to changes in the environment. As ion channels are evolutionary conserved proteins that all cells of all living creatures utilize to sense and adapt to variations of both extracellular and intracellular environments, it is not surprising that malfunction of ion channels increases disease susceptibility that often simulates ailments of getting older. This suggests that drugs targeting ion channels can hold promise for treating aging. However, in consideration of the fact that more than 400 genes encoding for ion channels subunits have been identified so far, the role of ion channels in aging and aging-related diseases remains significantly underex‐ plored. In addition, aging-dependent alteration of a particular ion channel appears to be organ and/or tissue-specific indicating that pharmacologic therapies targeting a specific ion channel should be tailored to a particular organ. 

The ultimate consequence of all diseases is pain which appears to get worse with age and can have serious negative impact on quality of life. In recent time, a substantial increased aware‐ ness on the critical role of ion channels in diseases and pain has been achieved so that ion channels are emerging as novel therapeutic targets in the treatment of pain. 

 

  • [67]  Wright EM. (2001) Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol, 280, F10-8.
  • [68]  WrightEM,HirayamaBA,LooDF.(2007)Activesugartransportinhealthanddisease. J Intern Med, 261, 32–43.
  • [69]  Hogan PG, Chen L, Nardone J, Rao A. (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev, 17, 2205–2232.
  • [70]  JohnsonCM,HillCS,ChawlaS,TreismanR,BadingH.(1997)Calciumcontrolsgene expression via three distinct pathways that can function independently of the Ras/ mitogen-activated protein kinases (ERKs) signaling cascade. J Neurosci, 17, 6189–6202.
  • [71]  Rao VR, Perez-Neut M, Kaja S, Gentile S. Voltage-gated ion channels in cancer cell proliferation. Cancers (Basel), 7, 849–875.
  • [72]  Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP. (2012) hERG K(+) channels: structure, function, and clinical significance. Physiol Rev, 92, 1393–1478.

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Ion Channels in Aging and Aging-Related Diseases 53 http://dx.doi.org/10.5772/63951 

  • [73]  Arcangeli A. (2005) Expression and role of hERG channels in cancer cells. Novartis Found Symp, 266, 225–232; discussion 232–234.
  • [74]  GanapathiSB,KesterM,ElmslieKS.(2009)State-dependentblockofHERGpotassium channels by R-roscovitine: implications for cancer therapy. Am J Physiol Cell Physiol, 296, C701-10.
  • [75]  Glassmeier G, Hempel K, Wulfsen I, Bauer CK, Schumacher U, Schwarz JR. (2012) Inhibition of HERG1 K+ channel protein expression decreases cell proliferation of human small cell lung cancer cells. Pflugers Arch, 463, 365–376.
  • [76]  LansuK,GentileS.Potassiumchannelactivationinhibitsproliferationofbreastcancer cells by activating a senescence program. Cell Death Dis, 4, e652.
  • [77]  Perez-NeutM,RaoVR,GentileS.hERG1/Kv11.1activationstimulatestranscriptionof p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism. Oncotarget.
  • [78]  Perez-NeutM,ShumA,CuevasBD,MillerR,GentileS.StimulationofhERG1channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells. Oncotarget, 6, 1631–1639.
  • [79]  Hayflick L, Moorhead PS. (1961) The serial cultivation of human diploid cell strains. Exp Cell Res, 25, 585–621.
  • [80]  Campisi J. (2000) Cancer, aging and cellular senescence. In Vivo, 14, 183–188.
  • [81]  Munoz-EspinD,SerranoM.(2014)Cellularsenescence:fromphysiologytopathology. Nat Rev Mol Cell Biol, 15, 482–496.
  • [82]  Rodier F, Campisi J. (2011) Four faces of cellular senescence. J Cell Biol, 192, 547–556.
  • [83]  LansuK,GentileS.(2013)Potassiumchannelactivationinhibitsproliferationofbreast cancer cells by activating a senescence program. Cell Death Dis, 4, e652.
  • [84]  Perez-Neut M, Rao VR, Gentile S. (2014) hERG1/Kv11.1 activation stimulates tran‐ scription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism. Oncotarget.
  • [85]  Perez-NeutM,ShumA,CuevasBD,MillerR,GentileS.(2014)StimulationofhERG1 channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells. Oncotarget, 6, 1631–1639.
  • [86]  LeongHS,RobertsonAE,StoletovK,LeithSJ,ChinCA,ChienAE,HagueMN,Ablack A, Carmine-Simmen K, McPherson VA, Postenka CO, Turley EA, Courtneidge SA, Chambers AF, Lewis JD. (2014) Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis. Cell Rep, 8, 1558–1570.
  • [87]  SontheimerH.(2008)Anunexpectedroleforionchannelsinbraintumormetastasis. Exp Biol Med (Maywood), 233, 779–791.

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54 Molecular Mechanisms of the Aging Process and Rejuvenation 

  • [88]  Pardo LA, del Camino D, Sanchez A, Alves F, Bruggemann A, Beckh S, Stuhmer W. (1999) Oncogenic potential of EAG K(+) channels. EMBO J, 18, 5540–5547.
  • [89]  WuX,ZhongD,LinB,ZhaiW,DingZ,WuJ.(2013)p38MAPKregulatestheexpression of ether a go-go potassium channel in human osteosarcoma cells. Radiol Oncol, 47, 42– 49.
  • [90]  HassanMS,AnsariJ,SpoonerD,HussainSA.(2010)Chemotherapyforbreastcancer (Review). Oncol Rep, 24, 1121–1131.
  • [91]  Michaud JE, Billups KL, Partin AW. (2015) Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk. Ther Adv Urol, 7, 378–387.
  • [92]  Gentile S, Darden T, Erxleben C, Romeo C, Russo A, Martin N, Rossie S, Armstrong DL. (2006) Rac GTPase signaling through the PP5 protein phosphatase. Proc Natl Acad Sci U S A, 103, 5202–5206.
  • [93]  SimonciniT,GenazzaniAR.(2003)Non-genomicactionsofsexsteroidhormones.Eur J Endocrinol, 148, 281–292.
  • [94]  StoreyNM,GentileS,UllahH,RussoA,MuesselM,ErxlebenC,ArmstrongDL.(2006) Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone. Proc Natl Acad Sci U S A, 103, 5197–5201.
  • [95]  DrazninB.(1988)Intracellularcalcium,insulinsecretion,andaction.AmJMed,85,44– 58.
  • [96]  KajaS,PayneAJ,BurroughsSL,KoulenP.(2013)Homer.In:EncyclopediaofSignaling Molecules (ed. S Choi). Springer.
  • [97]  WesthoffJH,HwangSY,DuncanRS,OzawaF,VolpeP,InokuchiK,KoulenP.(2003) Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling. Cell Calcium, 34, 261–269.
  • [98]  DuncanRS,HwangSY,KoulenP.(2005)EffectsofVesl/Homerproteinsonintracellular signaling. Exp Biol Med (Maywood), 230, 527–535.
  • [99]  HwangSY,WeiJ,WesthoffJH,DuncanRS,OzawaF,VolpeP,InokuchiK,KoulenP. (2003) Differential functional interaction of two Vesl/Homer protein isoforms with ryanodine receptor type 1: a novel mechanism for control of intracellular calcium signaling. Cell Calcium, 34, 177–184.
  • [100]  KajaS,YangSH,WeiJ,FujitaniK,LiuR,Brun-ZinkernagelAM,SimpkinsJW,Inokuchi K, Koulen P. (2003) Estrogen protects the inner retina from apoptosis and ischemia- induced loss of Vesl-1L/Homer 1c immunoreactive synaptic connections. Invest Ophthalmol Vis Sci, 44, 3155–3162.
  • [101]  PayneAJ,GerdesBC,NaumchukY,McCalleyAE,KajaS,KoulenP.(2013)Presenilins regulate the cellular activity of ryanodine receptors differentially through isotype- specific N-terminal cysteines. Exp Neurol, 250, 143–150.

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Ion Channels in Aging and Aging-Related Diseases 55 http://dx.doi.org/10.5772/63951 

  • [102]  PayneAJ,KajaS,KoulenP.(2015)Regulationofryanodinereceptor-mediatedcalcium signaling by presenilins. Receptors Clin Investig, 2, e449.
  • [103]  RybalchenkoV,HwangSY,RybalchenkoN,KoulenP.(2008)ThecytosolicN-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity. Int J Biochem Cell Biol, 40, 84–97.
  • [104]  HayrapetyanV,RybalchenkoV,RybalchenkoN,KoulenP.(2008)TheN-terminusof presenilin-2 increases single channel activity of brain ryanodine receptors through direct protein-protein interaction. Cell Calcium, 44, 507–518.27.
  • [105]  ChiamvimonvatN,O’RourkeB,KampTJ,KallenRG,HofmannF,FlockerziV,Marban E. (1995) Functional consequences of sulfhydryl modification in the pore-forming subunits of cardiovascular Ca2+ and Na+ channels. Circ Res, 76, 325–334.

 

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