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Potassium and Chloride Ion Channels in Cancer: A Novel Paradigm for Cancer Therapeutics

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Targets of Cancer Diagnosis and Treatment

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 183))

Abstract

Cancer is a collection of diseases caused by specific changes at the genomic level that support cell proliferation indefinitely. Traditionally, ion channels are known to control a variety of cellular processes including electrical signal generation and transmission, secretion, and contraction by controlling ionic gradients. However, recent studies had brought to light important facts on ion channels in cancer biology.

In this review we discuss the mechanism linking potassium or chloride ion channel activity to biochemical pathways controlling proliferation in cancer cells and the potential advantages of targeting ion channels as an anticancer therapeutic option.

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Abbreviations

AVD:

Apoptotic volume decrease

ER/PR:

Estrogen/progesterone receptors

GPER:

G protein estrogen receptor

HER2:

Human epidermal growth factor receptor 2

K2P:

Two-pore-domain potassium channel

Kir:

Inward-rectifier potassium channel

Kv:

Voltage-gated potassium channel

LRRC:

Leucine-rich repeat-containing

Vm:

Voltage membrane

VRAC:

Volume regulated anion channels

References

  • Accardi A (2015) Cell signaling. Lipids link ion channels and cancer. Science 349(6250):789–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agarwal JR, Griesinger F, Stuhmer W, Pardo LA (2010) The potassium channel ether a go-go is a novel prognostic factor with functional relevance in acute myeloid leukemia. Mol Cancer 9:18

    Article  PubMed  PubMed Central  Google Scholar 

  • Albertson DG (2006) Gene amplification in cancer. Trends Genet 22(8):447–455

    Article  CAS  PubMed  Google Scholar 

  • Ali NA, Wu J, Hochgrafe F, Chan H, Nair R, Ye S et al (2014) Profiling the tyrosine phosphoproteome of different mouse mammary tumour models reveals distinct, model-specific signalling networks and conserved oncogenic pathways. Breast Cancer Res 16(5):437

    Article  PubMed  PubMed Central  Google Scholar 

  • Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B et al (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 26(4):435–439

    Article  CAS  PubMed  Google Scholar 

  • Baffy G (2010) Uncoupling protein-2 and cancer. Mitochondrion 10(3):243–252

    Article  CAS  PubMed  Google Scholar 

  • Baffy G, Derdak Z, Robson SC (2011) Mitochondrial recoupling: a novel therapeutic strategy for cancer? Br J Cancer 105(4):469–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banderali U, Ehrenfeld J (1996) Heterogeneity of volume-sensitive chloride channels in basolateral membranes of A6 epithelial cells in culture. J Membr Biol 154(1):23–33

    Article  CAS  PubMed  Google Scholar 

  • Banderali U, Roy G (1992) Anion channels for amino-acids in Mdck cells. Am J Physiol 263(6):C1200–C1207

    Article  CAS  PubMed  Google Scholar 

  • Banderali U, Jayanthan A, Hoeksema KA, Narendran A, Giles WR (2012) Ion channels in pediatric CNS atypical teratoid/rhabdoid tumor (AT/RT) cells: potential targets for novel therapeutic agents. J Neurooncol 107(1):111–119

    Article  CAS  PubMed  Google Scholar 

  • Bentzen BH, Bahrke S, Wu K, Larsen AP, Odening KE, Franke G et al (2011) Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits. J Cardiovasc Pharmacol 57(2):223–230

    Article  CAS  PubMed  Google Scholar 

  • Bianchi L, Wible B, Arcangeli A, Taglialatela M, Morra F, Castaldo P et al (1998) Herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells? Cancer Res 58(4):815–822

    CAS  PubMed  Google Scholar 

  • Biasutto L, Azzolini M, Szabo I, Zoratti M (2016) The mitochondrial permeability transition pore in AD 2016: an update. Biochim Biophys Acta 1863(10):2515–2530

    Article  CAS  PubMed  Google Scholar 

  • Bill A, Gutierrez A, Kulkarni S, Kemp C, Bonenfant D, Voshol H et al (2015) ANO1/TMEM16A interacts with EGFR and correlates with sensitivity to EGFR-targeting therapy in head and neck cancer. Oncotarget 6(11):9173–9188

    Article  PubMed  PubMed Central  Google Scholar 

  • Binggeli R, Weinstein RC (1986) Membrane potentials and sodium channels: hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions. J Theor Biol 123(4):377–401

    Article  CAS  PubMed  Google Scholar 

  • Boonstra J, Mummery CL, Tertoolen LG, Van Der Saag PT, De Laat SW (1981) Cation transport and growth regulation in neuroblastoma cells. Modulations of K+ transport and electrical membrane properties during the cell cycle. J Cell Physiol 107(1):75–83

    Article  CAS  PubMed  Google Scholar 

  • Brevet M, Haren N, Sevestre H, Merviel P, Ouadid-Ahidouch H (2009a) DNA methylation of K(v)1.3 potassium channel gene promoter is associated with poorly differentiated breast adenocarcinoma. Cell Physiol Biochem 24(1–2):25–32

    Article  CAS  PubMed  Google Scholar 

  • Brevet M, Fucks D, Chatelain D, Regimbeau JM, Delcenserie R, Sevestre H et al (2009b) Deregulation of 2 potassium channels in pancreas adenocarcinomas: implication of KV1.3 gene promoter methylation. Pancreas 38(6):649–654

    Article  CAS  PubMed  Google Scholar 

  • Bulk E, Ay AS, Hammadi M, Ouadid-Ahidouch H, Schelhaas S, Hascher A et al (2015) Epigenetic dysregulation of KCa 3.1 channels induces poor prognosis in lung cancer. Int J Cancer 137(6):1306–1317

    Article  CAS  PubMed  Google Scholar 

  • Chernet BT, Levin M (2013) Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model. Dis Model Mech 6(3):595–607

    CAS  PubMed  PubMed Central  Google Scholar 

  • Choe S (2002) Potassium channel structures. Nat Rev Neurosci 3(2):115–121

    Article  CAS  PubMed  Google Scholar 

  • Cicek MS, Koestler DC, Fridley BL, Kalli KR, Armasu SM, Larson MC et al (2013) Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel. Hum Mol Genet 22(15):3038–3047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cone CD Jr (1969) Electroosmotic interactions accompanying mitosis initation in sarcoma cells in vitro. Trans N Y Acad Sci 31(4):404–427

    Article  PubMed  Google Scholar 

  • Cone CD Jr (1970) Variation of the transmembrane potential level as a basic mechanism of mitosis control. Oncology 24(6):438–470

    Article  CAS  PubMed  Google Scholar 

  • Cone CD Jr (1971) Unified theory on the basic mechanism of normal mitotic control and oncogenesis. J Theor Biol 30(1):151–181

    Article  CAS  PubMed  Google Scholar 

  • Crociani O, Guasti L, Balzi M, Becchetti A, Wanke E, Olivotto M et al (2003) Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells. J Biol Chem 278(5):2947–2955

    Article  CAS  PubMed  Google Scholar 

  • DeCoursey TE, Chandy KG, Gupta S, Cahalan MD (1984) Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis? Nature 307(5950):465–468

    Article  CAS  PubMed  Google Scholar 

  • Delierneux C, Kouba S, Shanmughapriya S, Potier-Cartereau M, Trebak M, Hempel N (2020) Mitochondrial calcium regulation of redox signaling in cancer. Cells (2):9

    Google Scholar 

  • Djamgoz MBA, Mycielska M, Madeja Z, Fraser SP, Korohoda W (2001) Directional movement of rat prostate cancer cells in direct-current electric field: involvement of voltagegated Na+ channel activity. J Cell Sci 114(Pt 14):2697–2705

    Article  CAS  PubMed  Google Scholar 

  • Du S, Yang L (2015) ClC-3 chloride channel modulates the proliferation and migration of osteosarcoma cells via AKT/GSK3beta signaling pathway. Int J Clin Exp Pathol 8(2):1622–1630

    PubMed  PubMed Central  Google Scholar 

  • Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H et al (2007) Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem 282(15):11221–11229

    Article  CAS  PubMed  Google Scholar 

  • Fujimoto M, Inoue T, Kito H, Niwa S, Suzuki T, Muraki K et al (2017) Transcriptional repression of HER2 by ANO1 Cl(−) channel inhibition in human breast cancer cells with resistance to trastuzumab. Biochem Biophys Res Commun 482(1):188–194

    Article  CAS  PubMed  Google Scholar 

  • Fukushiro-Lopes DF, Hegel AD, Rao V, Wyatt D, Baker A, Breuer EK et al (2018) Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer. Oncotarget 9(3):3321–3337

    Article  PubMed  Google Scholar 

  • Fukushiro-Lopes D, Hegel AD, Russo A, Senyuk V, Liotta M, Beeson GC et al (2020) Repurposing Kir6/SUR2 channel activator minoxidil to arrests growth of gynecologic cancers. Front Pharmacol 11:577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gentile S (2012) Ion channel phosphorylopathy: a link between genomic variation and human disease. ChemMedChem 7(10):1757–1761

    Article  CAS  PubMed  Google Scholar 

  • Gentile S (2016) hERG1 potassium channel in cancer cells: a tool to reprogram immortality. Eur Biophys J 45(7):649–655

    Article  CAS  PubMed  Google Scholar 

  • Gentile S, Darden T, Erxleben C, Romeo C, Russo A, Martin N et al (2006) Rac GTPase signaling through the PP5 protein phosphatase. Proc Natl Acad Sci U S A 103(13):5202–5206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M et al (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A 110(15):5887–5892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Godse NR, Khan N, Yochum ZA, Gomez-Casal R, Kemp C, Shiwarski DJ et al (2017) TMEM16A/ANO1 inhibits apoptosis via downregulation of Bim expression. Clin Cancer Res 23(23):7324–7332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez-Varela D, Zwick-Wallasch E, Knotgen H, Sanchez A, Hettmann T, Ossipov D et al (2007) Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitumor activity. Cancer Res 67(15):7343–7349

    Article  CAS  PubMed  Google Scholar 

  • Goswami C, Hucho T (2007) TRPV1 expression-dependent initiation and regulation of filopodia. J Neurochem 103(4):1319–1333

    Article  CAS  PubMed  Google Scholar 

  • Grasso D, Zampieri LX, Capeloa T, Van de Velde JA, Sonveaux P (2020) Mitochondria in cancer. Cell Stress 4(6):114–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gray LS, Perez-Reyes E, Gomora JC, Haverstick DM, Shattock M, McLatchie L et al (2004) The role of voltage gated T-type Ca2+ channel isoforms in mediating “capacitative” Ca2+ entry in cancer cells. Cell Calcium 36(6):489–497

    Article  CAS  PubMed  Google Scholar 

  • Grimm C, Bartel K, Vollmar AM, Biel M (2018) Endolysosomal cation channels and cancer – a link with great potential. Pharmaceuticals (Basel) 11(1)

    Google Scholar 

  • Guan LZ, Song Y, Gao J, Gao JJ, Wang KW (2016) Inhibition of calcium-activated chloride channel ANO1 suppresses proliferation and induces apoptosis of epithelium originated cancer cells. Oncotarget 7(48):78619–78630

    Article  PubMed  PubMed Central  Google Scholar 

  • Hartung F, Kruwel T, Shi X, Pfizenmaier K, Kontermann R, Chames P et al (2020) A novel anti-Kv10.1 nanobody fused to single-chain TRAIL enhances apoptosis induction in cancer cells. Front Pharmacol 11:686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hegle AP, Marble DD, Wilson GF (2006) A voltage-driven switch for ion-independent signaling by ether-a-go-go K+ channels. Proc Natl Acad Sci U S A 103(8):2886–2891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffmann EK, Lambert IH (2014) Ion channels and transporters in the development of drug resistance in cancer cells. Philos Trans R Soc Lond B Biol Sci 369(1638):20130109

    Article  PubMed  PubMed Central  Google Scholar 

  • Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N et al (2014) Drug resistance in cancer: an overview. Cancers (Basel) 6(3):1769–1792

    Article  Google Scholar 

  • Iitaka D, Shiozaki A, Ichikawa D, Kosuga T, Komatsu S, Okamoto K et al (2012) Blockade of chloride ion transport enhances the cytocidal effect of hypotonic solution in gastric cancer cells. J Surg Res 176(2):524–534

    Article  CAS  PubMed  Google Scholar 

  • Innamaa A, Jackson L, Asher V, Van Shalkwyk G, Warren A, Hay D et al (2013) Expression and prognostic significance of the oncogenic K2P potassium channel KCNK9 (TASK-3) in ovarian carcinoma. Anticancer Res 33(4):1401–1408

    CAS  PubMed  Google Scholar 

  • Jentsch TJ, Lutter D, Planells-Cases R, Ullrich F, Voss FK (2016) VRAC: molecular identification as LRRC8 heteromers with differential functions. Pflugers Archiv Eur J Physiol 468(3):385–393

    Article  CAS  Google Scholar 

  • Jia LH, Liu W, Guan LZ, Lu M, Wang KW (2015) Inhibition of calcium-activated chloride channel ANO1/TMEM16A suppresses tumor growth and invasion in human lung cancer. Plos One 10(8)

    Google Scholar 

  • Johnstone BM (1959) Micro-electrode penetration of ascites tumour cells. Nature 183(4658):411

    Article  CAS  PubMed  Google Scholar 

  • Kaczorowski GJ, McManus OB, Priest BT, Garcia ML (2008) Ion channels as drug targets: the next GPCRs. J Gen Physiol 131(5):399–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kapur N, Mignery GA, Banach K (2007) Cell cycle-dependent calcium oscillations in mouse embryonic stem cells. Am J Physiol Cell Physiol 292(4):C1510–C1518

    Article  CAS  PubMed  Google Scholar 

  • Kischel P, Girault A, Rodat-Despoix L, Chamlali M, Radoslavova S, Abou Daya H et al (2019) Ion channels: new actors playing in chemotherapeutic resistance. Cancers (Basel) 11(3)

    Google Scholar 

  • Koster AK, Wood CAP, Thomas-Tran R, Chavan TS, Almqvist J, Choi KH et al (2018) A selective class of inhibitors for the CLC-Ka chloride ion channel. Proc Natl Acad Sci U S A 115(21):E4900–E49E9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kudou M, Shiozaki A, Kosuga T, Ichikawa D, Konishi H, Morimura R et al (2016) Inhibition of regulatory volume decrease enhances the cytocidal effect of hypotonic shock in hepatocellular carcinoma. J Cancer 7(11):1524–1533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lallet-Daher H, Wiel C, Gitenay D, Navaratnam N, Augert A, Le Calve B et al (2013) Potassium channel KCNA1 modulates oncogene-induced senescence and transformation. Cancer Res 73(16):5253–5265

    Article  CAS  PubMed  Google Scholar 

  • Lansu K, Gentile S (2013) Potassium channel activation inhibits proliferation of breast cancer cells by activating a senescence program. Cell Death Dis 4:e652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leanza L, Henry B, Sassi N, Zoratti M, Chandy KG, Gulbins E et al (2012) Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells. EMBO Mol Med 4(7):577–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leanza L, Trentin L, Becker KA, Frezzato F, Zoratti M, Semenzato G et al (2013) Clofazimine, Psora-4 and PAP-1, inhibitors of the potassium channel Kv1.3, as a new and selective therapeutic strategy in chronic lymphocytic leukemia. Leukemia 27(8):1782–1785

    Article  CAS  PubMed  Google Scholar 

  • Leanza L, Venturini E, Kadow S, Carpinteiro A, Gulbins E, Becker KA (2015) Targeting a mitochondrial potassium channel to fight cancer. Cell Calcium 58(1):131–138

    Article  CAS  PubMed  Google Scholar 

  • Leanza L, Manago A, Zoratti M, Gulbins E, Szabo I (2016) Pharmacological targeting of ion channels for cancer therapy: In vivo evidences. Biochim Biophys Acta 1863(6 Pt B):1385–1397

    Article  CAS  PubMed  Google Scholar 

  • Leanza L, Romio M, Becker KA, Azzolini M, Trentin L, Manago A et al (2017) Direct pharmacological targeting of a mitochondrial ion channel selectively kills tumor cells in vivo. Cancer Cell 31(4):516–531.e10

    Article  CAS  PubMed  Google Scholar 

  • Lepple-Wienhues A, Berweck S, Bohmig M, Leo CP, Meyling B, Garbe C et al (1996) K+ channels and the intracellular calcium signal in human melanoma cell proliferation. J Membr Biol 151(2):149–157

    Article  CAS  PubMed  Google Scholar 

  • Levin M (2012) Molecular bioelectricity in developmental biology: new tools and recent discoveries: control of cell behavior and pattern formation by transmembrane potential gradients. Bioessays 34(3):205–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levin M (2014) Molecular bioelectricity: how endogenous voltage potentials control cell behavior and instruct pattern regulation in vivo. Mol Biol Cell 25(24):3835–3850

    Article  PubMed  PubMed Central  Google Scholar 

  • Li M, Wu DB, Wang J (2013) Effects of volume-activated chloride channels on the invasion and migration of human endometrial cancer cells. Eur J Gynaecol Oncol 34(1):60–64

    PubMed  Google Scholar 

  • Lobikin M, Chernet B, Lobo D, Levin M (2012) Resting potential, oncogene-induced tumorigenesis, and metastasis: the bioelectric basis of cancer in vivo. Phys Biol 9(6):065002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loibl S, Marme F, Martin M, Untch M, Bonnefoi H, Kim SB et al (2021) Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer-the penelope-B trial. J Clin Oncol:JCO2003639

    Google Scholar 

  • Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B (2017) The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull 7(3):339–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao JW, Yuan J, Wang LW, Zhang HF, Jin XB, Zhu JY et al (2013) Tamoxifen inhibits migration of estrogen receptor-negative hepatocellular carcinoma cells by blocking the swelling-activated chloride current. J Cell Physiol 228(5):991–1001

    Article  CAS  PubMed  Google Scholar 

  • Marino AA, Morris DM, Schwalke MA, Iliev IG, Rogers S (1994) Electrical potential measurements in human breast cancer and benign lesions. Tumour Biol 15(3):147–152

    Article  CAS  PubMed  Google Scholar 

  • Menendez ST, Villaronga MA, Rodrigo JP, Alvarez-Teijeiro S, Garcia-Carracedo D, Urdinguio RG et al (2012a) Frequent aberrant expression of the human ether a go-go (hEAG1) potassium channel in head and neck cancer: pathobiological mechanisms and clinical implications. J Mol Med (Berl) 90(10):1173–1184

    Article  CAS  Google Scholar 

  • Menendez ST, Rodrigo JP, Alvarez-Teijeiro S, Villaronga MA, Allonca E, Vallina A et al (2012b) Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas. Mod Pathol 25(8):1069–1078

    Article  CAS  PubMed  Google Scholar 

  • Morais Cabral JH, Lee A, Cohen SL, Chait BT, Li M, Mackinnon R (1998) Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95(5):649–655

    Article  CAS  PubMed  Google Scholar 

  • Morokuma J, Blackiston D, Adams DS, Seebohm G, Trimmer B, Levin M (2008) Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells. Proc Natl Acad Sci U S A 105(43):16608–16613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mu D, Chen L, Zhang X, See LH, Koch CM, Yen C et al (2003) Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell 3(3):297–302

    Article  CAS  PubMed  Google Scholar 

  • Munaron L, Antoniotti S, Lovisolo D (2004) Intracellular calcium signals and control of cell proliferation: how many mechanisms? J Cell Mol Med 8(2):161–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Munoz-Espin D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15(7):482–496

    Article  CAS  PubMed  Google Scholar 

  • Nako Y, Shiozaki A, Ichikawa D, Komatsu S, Konishi H, Iitaka D et al (2012) Enhancement of the cytocidal effects of hypotonic solution using a chloride channel blocker in pancreatic cancer cells. Pancreatology 12(5):440–448

    Article  CAS  PubMed  Google Scholar 

  • Ng EY, Sree SV, Ng KH, Kaw G (2008) The use of tissue electrical characteristics for breast cancer detection: a perspective review. Technol Cancer Res Treat 7(4):295–308

    Article  CAS  PubMed  Google Scholar 

  • O’Grady SM, Lee SY (2005) Molecular diversity and function of voltage-gated (Kv) potassium channels in epithelial cells. Int J Biochem Cell Biol 37(8):1578–1594

    Article  PubMed  Google Scholar 

  • Ozkucur N, Perike S, Sharma P, Funk RH (2011) Persistent directional cell migration requires ion transport proteins as direction sensors and membrane potential differences in order to maintain directedness. BMC Cell Biol 12:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Pardo LA (2004) Voltage-gated potassium channels in cell proliferation. Physiology (Bethesda) 19:285–292

    CAS  Google Scholar 

  • Pardo LA, del Camino D, Sanchez A, Alves F, Bruggemann A, Beckh S et al (1999) Oncogenic potential of EAG K(+) channels. EMBO J 18(20):5540–5547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parrasia S, Rossa A, Varanita T, Checchetto V, De Lorenzi R, Zoratti M et al (2021) An Angiopep2-PAPTP construct overcomes the blood-brain barrier. New perspectives against brain tumors. Pharmaceuticals (Basel) 14(2)

    Google Scholar 

  • Pedemonte N, Galietta LJ (2014) Structure and function of TMEM16 proteins (anoctamins). Physiol Rev 94(2):419–459

    Article  CAS  PubMed  Google Scholar 

  • Perez-Neut M, Shum A, Cuevas BD, Miller R, Gentile S (2015a) Stimulation of hERG1 channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells. Oncotarget 6(3):1631–1639

    Article  PubMed  PubMed Central  Google Scholar 

  • Perez-Neut M, Rao VR, Haar L, Jones KW, Gentile S (2015b) Current and potential antiarrhythmic drugs targeting voltage-gated cardiac ion channels. Cardiol Pharmacol 4(139)

    Google Scholar 

  • Perez-Neut M, Haar L, Rao V, Santha S, Lansu K, Rana B et al (2016a) Activation of hERG3 channel stimulates autophagy and promotes cellular senescence in melanoma. Oncotarget 7(16):21991–22004

    Article  PubMed  PubMed Central  Google Scholar 

  • Perez-Neut M, Rao VR, Gentile S (2016b) hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism. Oncotarget 7(37):58893–58902

    Google Scholar 

  • Peruzzo R, Mattarei A, Azzolini M, Becker-Flegler KA, Romio M, Rigoni G et al (2020) Insight into the mechanism of cytotoxicity of membrane-permeant psoralenic Kv1.3 channel inhibitors by chemical dissection of a novel member of the family. Redox Biol 37:101705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Planells-Cases R, Lutter D, Guyader C, Gerhards NM, Ullrich F, Elger DA et al (2015) Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J 34(24):2993–3008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plummer HK 3rd, Dhar MS, Cekanova M, Schuller HM (2005) Expression of G-protein inwardly rectifying potassium channels (GIRKs) in lung cancer cell lines. BMC Cancer 5:104

    Article  PubMed  PubMed Central  Google Scholar 

  • Rao VR, Perez-Neut M, Kaja S, Gentile S (2015) Voltage-gated ion channels in cancer cell proliferation. Cancers (Basel) 7(2):849–875

    Article  CAS  Google Scholar 

  • Ryland KE, Hawkins AG, Weisenberger DJ, Punj V, Borinstein SC, Laird PW et al (2016) Promoter methylation analysis reveals that KCNA5 ion channel silencing supports Ewing sarcoma cell proliferation. Mol Cancer Res 14(1):26–34

    Article  CAS  PubMed  Google Scholar 

  • Schwab A, Wulf A, Schulz C, Kessler W, Nechyporuk-Zloy V, Romer M et al (2006) Subcellular distribution of calcium-sensitive potassium channels (IK1) in migrating cells. J Cell Physiol 206(1):86–94

    Article  CAS  PubMed  Google Scholar 

  • Schwab A, Fabian A, Hanley PJ, Stock C (2012) Role of ion channels and transporters in cell migration. Physiol Rev 92(4):1865–1913

    Article  CAS  PubMed  Google Scholar 

  • Serrano-Novillo C, Capera J, Colomer-Molera M, Condom E, Ferreres JC, Felipe A (2019) Implication of voltage-gated potassium channels in neoplastic cell proliferation. Cancers (Basel) 11(3)

    Google Scholar 

  • Shennan DB (2008) Swelling-induced taurine transport: relationship with chloride channels, anion-exchangers and other swelling-activated transport pathways. Cell Physiol Biochem 21(1–3):15–28

    Article  CAS  PubMed  Google Scholar 

  • Struski S, Doco-Fenzy M, Cornillet-Lefebvre P (2002) Compilation of published comparative genomic hybridization studies. Cancer Genet Cytogenet 135(1):63–90

    Article  CAS  PubMed  Google Scholar 

  • Sui YJ, Sun MY, Wu F, Yang LF, Di WH, Zhang GZ et al (2014) Inhibition of TMEM16A expression suppresses growth and invasion in human colorectal cancer cells. Plos One 9(12)

    Google Scholar 

  • Sun J, Chu Z, Moenter SM (2010) Diurnal in vivo and rapid in vitro effects of estradiol on voltage-gated calcium channels in gonadotropin-releasing hormone neurons. J Neurosci 30(11):3912–3923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo I, Bock J, Jekle A, Soddemann M, Adams C, Lang F et al (2005) A novel potassium channel in lymphocyte mitochondria. J Biol Chem 280(13):12790–12798

    Article  CAS  PubMed  Google Scholar 

  • Szabo I, Bock J, Grassme H, Soddemann M, Wilker B, Lang F et al (2008) Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes. Proc Natl Acad Sci U S A 105(39):14861–14866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo I, Soddemann M, Leanza L, Zoratti M, Gulbins E (2011) Single-point mutations of a lysine residue change function of Bax and Bcl-xL expressed in Bax- and Bak-less mouse embryonic fibroblasts: novel insights into the molecular mechanisms of Bax-induced apoptosis. Cell Death Differ 18(3):427–438

    Article  CAS  PubMed  Google Scholar 

  • Szabo I, Trentin L, Trimarco V, Semenzato G, Leanza L (2015) Biophysical characterization and expression analysis of Kv1.3 potassium channel in primary human leukemic B cells. Cell Physiol Biochem 37(3):965–978

    Article  CAS  PubMed  Google Scholar 

  • Than BL, Goos JA, Sarver AL, O'Sullivan MG, Rod A, Starr TK et al (2014) The role of KCNQ1 in mouse and human gastrointestinal cancers. Oncogene 33(29):3861–3868

    Article  CAS  PubMed  Google Scholar 

  • Tokuoka S, Morioka H (1957) The membrane potential of the human cancer and related cells. I Gan 48(4):353–354

    CAS  PubMed  Google Scholar 

  • Vallejo-Gracia A, Bielanska J, Hernandez-Losa J, Castellvi J, Ruiz-Marcellan MC, Ramon y Cajal S et al (2013) Emerging role for the voltage-dependent K+ channel Kv1.5 in B-lymphocyte physiology: expression associated with human lymphoma malignancy. J Leukoc Biol 94(4):779–789

    Article  CAS  PubMed  Google Scholar 

  • Venturini E, Leanza L, Azzolini M, Kadow S, Mattarei A, Weller M et al (2017) Targeting the potassium channel Kv1.3 kills glioblastoma cells. Neurosignals 25(1):26–38

    Article  PubMed  Google Scholar 

  • Villalonga N, Martinez-Marmol R, Roura-Ferrer M, David M, Valenzuela C, Soler C et al (2008) Cell cycle-dependent expression of Kv1.5 is involved in myoblast proliferation. Biochim Biophys Acta 1783(5):728–736

    Article  CAS  PubMed  Google Scholar 

  • Voss FK, Ullrich F, Munch J, Lazarow K, Lutter D, Mah N et al (2014) Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344(6184):634–638

    Article  CAS  PubMed  Google Scholar 

  • Wang Z (2004) Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflugers Arch 448(3):274–286

    Article  CAS  PubMed  Google Scholar 

  • Wang XT, Nagaba Y, Cross HS, Wrba F, Zhang L, Guggino SE (2000) The mRNA of L-type calcium channel elevated in colon cancer: protein distribution in normal and cancerous colon. Am J Pathol 157(5):1549–1562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang H, Zhang Y, Cao L, Han H, Wang J, Yang B et al (2002) HERG K+ channel, a regulator of tumor cell apoptosis and proliferation. Cancer Res 62(17):4843–4848

    CAS  PubMed  Google Scholar 

  • Wang W, Gao Q, Yang M, Zhang X, Yu L, Lawas M et al (2015) Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. Proc Natl Acad Sci U S A 112(11):E1373–E1381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei JF, Wei L, Zhou X, Lu ZY, Francis K, Hu XY et al (2008) Formation of Kv2.1-FAK complex as a mechanism of FAK activation, cell polarization and enhanced motility. J Cell Physiol 217(2):544–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wright SH (2004) Generation of resting membrane potential. Adv Physiol Educ 28(1–4):139–142

    Article  PubMed  Google Scholar 

  • Wu H, Wang H, Guan S, Zhang J, Chen Q, Wang X et al (2017) Cell-specific regulation of proliferation by Ano1/TMEM16A in breast cancer with different ER, PR, and HER2 status. Oncotarget 8(49):84996–85013

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu H, Ren D (2015) Lysosomal physiology. Annu Rev Physiol 77:57–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu HX, Martinoia E, Szabo I (2015) Organellar channels and transporters. Cell Calcium 58(1):1–10

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang B, Cao L, Liu B, McCaig CD, Pu J (2013) The transition from proliferation to differentiation in colorectal cancer is regulated by the calcium activated chloride channel A1. PLos One 8(4)

    Google Scholar 

  • Yang H, Ma L, Wang Y, Zuo W, Li B, Yang Y et al (2018) Activation of ClC-3 chloride channel by 17beta-estradiol relies on the estrogen receptor alpha expression in breast cancer. J Cell Physiol 233(2):1071–1081

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Li H, Liu E, Guang Y, Yang L, Mao J et al (2014) The AQP-3 water channel and the ClC-3 chloride channel coordinate the hypotonicity-induced swelling volume in nasopharyngeal carcinoma cells. Int J Biochem Cell Biol 57:96–107

    Article  CAS  PubMed  Google Scholar 

  • Zheng F, Li H, Du W, Huang S (2009) Role of hERG1 K(+) channels in leukemia cells as a positive regulator in SDF-1a-induced proliferation. Hematology 16(3):177–184

    Google Scholar 

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Authors and Affiliations

  1. Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, ON, Canada

    Umberto Banderali

  2. Department of Biology, University of Padova, Padova, Italy

    Luigi Leanza

  3. Department of Hematology and Oncology, University of Illinois Chicago, Chicago, IL, USA

    Najmeh Eskandari & Saverio Gentile

Authors
  1. Umberto Banderali
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  2. Luigi Leanza
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  3. Najmeh Eskandari
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  4. Saverio Gentile
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Corresponding author

Correspondence to Saverio Gentile .

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Editors and Affiliations

  1. Medizinische Hochschule Hannover, Zentrum für Innere Medizin, Hannover, Germany

    Christian Stock

  2. Max-Planck-Institut für Multidisziplinäre Naturwissenschaften, Göttingen, Germany

    Luis A. Pardo

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Banderali, U., Leanza, L., Eskandari, N., Gentile, S. (2021). Potassium and Chloride Ion Channels in Cancer: A Novel Paradigm for Cancer Therapeutics. In: Stock, C., Pardo, L.A. (eds) Targets of Cancer Diagnosis and Treatment. Reviews of Physiology, Biochemistry and Pharmacology, vol 183. Springer, Cham. https://doi.org/10.1007/112_2021_62

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