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Potassium Channels in Pancreatic Cancer

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Potassium Channels in Pancreatic Cancer Potassium channels in pancreatic cancer Authors: Abstract Mikio Hayashi Pancreatic duct adenocarcinoma accounts for Department of Physiology, approximately 90% of pancreatic cancers and has a Kansai Medical University, 5-1 very poor prognosis. Several K+ channels have Shimmachi 2, Hirakata, Osaka been suggested as hallmarks for adenocarcinoma. 573-1010, Japan. This review focuses on molecular candidates of E-mail: + [email protected] functional K channels in pancreatic adenocarcinoma, including KCNN4 (KCa3.1), Hiroko Matsuda KCNJ3 (Kir3.1), KCNA3 (Kv1.3), KCNA5 (Kv1.5), Department of Physiology, KCNH1 (K 10.1), and KCNK5 (K 5.1). We Kansai Medical University, 5-1 v 2P + Shimmachi 2, Hirakata, Osaka provide an overview of K channels with respect to 573-1010, Japan. their electrophysiological and pharmacological E-mail: characteristics and tissue expression, in addition to [email protected] their identification and functions in pancreatic Corresponding Author: adenocarcinomas. We conclude by discussing some Mikio Hayashi, PhD outstanding questions and future directions in Tel. +81-72-804-2321 pancreatic K+ channel research with respect to the Fax: +81-72-804-2329 treatment of pancreatic cancer. E-mail: [email protected] Keywords: cancer, EAG1, GIRK1, pancreas, SK4, TASK-2. Conflicts of interst: None declared. Abbreviations: No funding was provided for EC50, half maximal effective concentration; HERG, this research. human ether-à-go-go related gene; Kd, dissociation constant; Ki, inhibitory constant; PKC, protein kinase C; V1/2, half-maximal voltage. Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer 1. Introduction present in every cell. They set the cell membrane potential and thereby regulate Pancreatic duct adenocarcinoma the excitability of neurons and myocytes accounts for approximately 90% of as well as the transport of ions and water pancreatic cancers and has a very poor in epithelia. Duct epithelial cells in the prognosis. As reported in the World – pancreas secrete a HCO3 -rich pancreatic Cancer Report 2014 by the World Health juice that neutralizes acid chyme in the Organization, 25% of patients survive for duodenum. K+ channels are clearly one year and 5% for five years after being important for setting the resting diagnosed. Surgical resection of the membrane potential and providing the primary tumor remains the only option for driving force for anion exit and fluid long-term survival; however, candidates secretion in the epithelium [27, 28, 72]. for this surgery represent a very low Several K+ channels have been suggested percentage of all patients. as hallmarks for cancer, including Chemotherapy and radiation therapy are pancreatic duct adenocarcinoma [63]. frequently insufficient and controversial for the treatment of inoperable patients. It currently remains unknown + Thus, novel molecular targets for the whether many of the K channels development of alternative therapies are identified to date are functional in urgently required [31, 59]. pancreatic duct adenocarcinoma, and if they have potential as molecular targets Ion channels have been associated for therapies. The aim of this review is with the malignant phenotype of cancer to provide an overview of K+ channels cells and contribute to virtually all basic with respect to their electrophysiological cellular processes, including their crucial and pharmacological characteristics as roles in maintaining tissue homeostasis well as tissue expression. We also address such as proliferation, differentiation, and some outstanding questions and future apoptosis [60]. Potassium (K+) channels directions in the development of cancer are important membrane proteins that are therapies. Copyright 2016 KEI Journals. All Rights Reserved Page │2 Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer 2. KCNN4 (KCa3.1, SK4) charybdotoxin (2–28 nM), TRAM-34 (20 2.1. Expression and function nM), and clotrimazole (25–150 nM) [9, 32, 35, 76, 81, 82]. KCa3.1 currents were also KCNN4 coding for the KCa3.1 activated by DC-EBIO (Kd value of 0.8 protein was cloned from the placenta and μM) and 1-EBIO (15–84 μM) [35, 68, 76, pancreas [32, 39]. The functional 81]. expression of the KCNN4 gene has been detected in erythrocytes [61], T 2.3. Expression in cancer lymphocytes [5], microglia [40], airway Electrophysiological studies epithelial cells [2], and pancreatic ducts demonstrated the functional expression of [28, 29, 77]. Single-channel openings KCa3.1 in BxPC-3 and MiaPaCa-2 human have been observed at positive and pancreatic carcinoma cell lines. The negative membrane potentials, and gating functional expression of KCa3.1 channels showed no significant voltage dependency. in BxPC-3 and MiaPaCa-2 cells was 3- to The single-channel current–voltage 6-fold higher than that in the Panc-1 relationship showed weak inward pancreatic cancer cell line. KCa3.1 currents rectification with conductance of 30–54 were inhibited by charybdotoxin, pS in heterologous expression systems [32, clotrimazole, and TRAM-34 with Ki 35, 76]. KCa3.1 channels were shown to be values of 10 nM, 40 nM, and 20 nM, activated by intracellular Ca2+ respectively. The proliferation of BxPC-3 concentrations with EC50 values of and MiaPaCa-2 was completely inhibited 0.1–0.3 μM [32, 39, 76, 81]. In addition, by 10 μM clotrimazole or TRAM-34. KCa3.1 channels were regulated by KCNN4 mRNA levels in BxPC-3 and cAMP/cAMP-dependent protein kinase MiaPaCa-2 cells were 3- to 8-fold higher signaling pathway [19, 26, 61]. than those in Panc-1, corresponding to the 2.2. Pharmacology values obtained in electrophysiological analyses. Eight out of 9 samples (89%) of KCa3.1 currents were inhibited by primary pancreatic tumors were found to maurotoxin (Ki value of 1 nM), contain 6- to 66-fold higher levels of Copyright 2016 KEI Journals. All Rights Reserved Page │3 Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer KCNN4 mRNA [34]. KCa3.1 channel conductance of 35–42 pS in heterologous immunoreactivity was shown to be expression systems [46, 47]. Kir3.1 localized in the basolateral and luminal channels were previously reported to be membranes in a monolayer of Capan-1, a activated by G protein βγ subunits [64]. human pancreas adenocarcinoma cell line; 3.2. Pharmacology however, its expression appeared to be Kir3.1/Kir3.x currents were inhibited stronger in the luminal membrane. by tertiapin (Ki value of 8 nM), Consistent with this finding, the tertiapin-Q (13 nM), pimozide (2–3 μM), short-circuit current of the Capan-1 cell fluoxetine (7 μM), sertraline (12 μM), monolayer was enhanced by the KCa3.1 duloxetine (15–17 μM), clomipramine channel activator DC-EBIO (100 μM) in (18–24 μM), and amoxapine (18–38 μM) luminal or basolateral bathing solution [28, [37, 38, 42–45]. 77]. 3.3. Expression in cancer 3. KCNJ3 (Kir3.1, GIRK1) Kir3.1 immunoreactivity was shown 3.1. Expression and function to be localized in the apical cytoplasm in KCNJ3 coding for the Kir3.1 protein epithelial cells of the normal pancreas and was isolated from the heart cDNA library tumor cells of adenocarcinomas. The [47]. The Kir3.1 protein is generally expression of Kir3.1 was stronger in incorporated into heteromers with other adenocarcinomas than in normal tissue. Kir3.x subunits in order to form functional Consistent with this histochemical channels in native cells and tissues [46]. evaluation, KCNJ3 mRNA levels were The functional expression of the KCNJ3 8-fold higher in pancreatic adeno- gene has been detected in the heart [46], carcinomas than in normal tissue. brain [50], pituitary gland [55], and However, no correlation was observed endocrine pancreas [33]. The single- between Kir3.1 expression and metastasis channel current–voltage relationship [7]. showed inward rectification with Copyright 2016 KEI Journals. All Rights Reserved Page │4 Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer 4. KCNA3 (Kv1.3) CP339818 (150 nM), and UK78282 (200 4.1. Expression and function nM) [11, 24, 25, 83]. 4.3. Expression in cancer KCNA3 coding for the Kv1.3 protein was isolated from the cortex and T Kv1.3 immunoreactivity was shown lymphocyte cDNA library [3, 74]. The to be localized in the cytoplasm in functional expression of the KCNA3 gene epithelial cells of the normal pancreas. has been detected in the cortex [74], T The expression of Kv1.3 was weaker in lymphocytes [3, 23], and oligodendrocytes adenocarcinomas than in normal tissue [6, [12]. Kv1.3 currents were activated at 7]. Additionally, KCNA3 mRNA levels voltages more positive than −50 mV and were slightly decreased in pancreatic V1/2 was −35 mV [23]. Single-channel cancer. The weak expression of Kv1.3 was conductance was 13 pS in heterologous associated with metastasis to local lymph expression systems [23]. Native Kv1.3 nodes and/or distant organs [7]. channels were up-regulated by PKC 5. KCNA5 (Kv1.5) phosphorylation in lymphocytes, whereas they were down-regulated by cAMP/PKA 5.1. Expression and function signaling [13, 48]. KCNA5 coding for the Kv1.5 protein 4.2. Pharmacology was isolated from the brain cDNA library [75]. The functional expression of the Kv1.3 currents were inhibited by KCNA5 gene has been detected in skeletal ADWX-1 (Ki value of 2 pM), ShK (11 and cardiac muscles [54, 70] and islets pM), HsTx1 (12 pM), BmKTX-D33H (15 [62]. Kv1.5 currents were activated at pM), Pi2 (50 pM), ShK-Dap22 (52 pM), voltages more positive than −30 mV and margatoxin (110 pM), agitoxin-1 (200 V1/2 was −13 mV [54, 70]. Single- pM), Pi3 (500 pM), kaliotoxin (650 pM), channel conductance was 8 pS in naltrexone (1 nM), charybdotoxin (3 nM), heterologous expression systems [54]. Pi1 (11 nM), BgK (39 nM), correolide (90 The activation of PKC and AMP-activated nM), sulfamidbenzamidoindane (100 nM), protein kinase reduced the surface Copyright 2016 KEI Journals.
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