Expression of KATP channels in human cervical cancer: Potential tools for diagnosis and therapy

Vázquez‑Sánchez,Alma  Yolanda; Hinojosa,Luz  María; Parraguirre‑Martínez,Sara; González,Aarón; Morales,Flavia; Montalvo,Gonzalo; Vera,Eunice; Hernández‑Gallegos,Elisabeth; Camacho,Javier

doi:10.3892/ol.2018.8165

Expression of KATP channels in human cervical cancer: Potential tools for diagnosis and therapy

Authors:
- Alma Yolanda Vázquez‑Sánchez
- Luz María Hinojosa
- Sara Parraguirre‑Martínez
- Aarón González
- Flavia Morales
- Gonzalo Montalvo
- Eunice Vera
- Elisabeth Hernández‑Gallegos
- Javier Camacho
View Affiliations

Affiliations: Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute, Mexico City 07360, Mexico, Service of Dysplasia, Gynecology and Obstetrics, ‘Dr Manuel Gea González’ Hospital General, Mexico City 14080, Mexico, Division of Anatomical Pathology, ‘Dr Manuel Gea González’ Hospital General, Mexico City 14080, Mexico, Service of Colposcopy, Instituto Nacional de Cancerología, Mexico City 14080, Mexico, Medical Oncology, Instituto Nacional de Cancerología, Mexico City 14080, Mexico, Service of Gynecology, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
Published online on: March 2, 2018 https://doi.org/10.3892/ol.2018.8165
Pages: 6302-6308
Copyright: © Vázquez‑Sánchez et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Various ion channels, including ATP-sensitive potassium (KATP) channels, are expressed in cancer and have been suggested as potential tumor markers and therapeutic targets. KATP channels are composed of at least two types of subunit, an inwardly rectifying K+ channel (Kir6.x) and a sulfonylurea receptor (SUR). However, the association between KATP channels and cervical cancer remains elusive. The present study determined that the Kir6.2, SUR1 and SUR2 subunits are expressed in cervical cancer cell lines and/or human biopsies. The potential association of subunit expression with tumor differentiation and invasion was analyzed. The effect of the KATP channel blocker glibenclamide on the proliferation of cervical cancer cell lines was also studied. Five cervical cancer cell lines, two primary cultures of cervical cancer cells, one normal keratinocyte cell line and 74 human biopsies were used in the experiments. The mRNA and protein levels of the Kir6.2 subunit were assessed by reverse transcription‑polymerase chain reaction and immunochemistry, respectively. Cell proliferation was evaluated by MTT assay. Kir6.2 subunit overexpression compared with control, was observed in some cervical cancer cell lines and cervical tumor tissues. Additionally, increased KATP channel expression was observed in high‑grade, poorly differentiated and invasive human cervical cancer biopsies. Kir6.2 subunit expression was not observed in the majority of the non‑cancerous cervical tissues. The effect of the KATP channel blocker glibenclamide on the proliferation of five different cervical cancer cell lines was studied, revealing that as Kir6.2 mRNA expression increased, the inhibitory effect of glibenclamide also increased. The results of the present study suggest, for the first time to the best of our knowledge, that the KATP channel subunits, Kir6.2 and SUR2, could potentially represent tools for diagnosing and treating cervical cancer.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Moore DH: Cervical cancer. Obstet Gynecol. 107:1152–1161. 2006. View Article : Google Scholar : PubMed/NCBI
3	Cadron I, Van Gorp T, Amant F, Leunen K, Neven P and Vergote I: Chemotherapy for recurrent cervical cancer. Gynecol Oncol. 107 1 Suppl 1:S113–S118. 2007. View Article : Google Scholar : PubMed/NCBI
4	Dubois JM and Rouzaire-Dubois B: Role of potassium channels in mitogenesis. Prog Biophys Mol Biol. 59:1–21. 1993. View Article : Google Scholar : PubMed/NCBI
5	Pardo LA and Stühmer W: The roles of K(+) channels in cancer. Nat Rev Cancer. 14:39–48. 2014. View Article : Google Scholar : PubMed/NCBI
6	Clement JP IV, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar-Bryan L and Bryan J: Association and stoichiometry of K(ATP) channel subunits. Neuron. 18:827–838. 1997. View Article : Google Scholar : PubMed/NCBI
7	Babenko AP, Aguilar-Bryan L and Bryan J: A view of sur/KIR6.X, KATP channels. Annu Rev Physiol. 60:667–687. 1998. View Article : Google Scholar : PubMed/NCBI
8	Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J and Seino S: A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K⁺ channels. Neuron. 16:1011–1017. 1996. View Article : Google Scholar : PubMed/NCBI
9	Aguilar-Bryan L and Bryan J: Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev. 20:101–135. 1999. View Article : Google Scholar : PubMed/NCBI
10	Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP IV, Boyd AE III, González G, Herrera-Sosa H, Nguy K, Bryan J and Nelson DA: Cloning of the beta cell high-affinity sulfonylurea receptor: A regulator of insulin secretion. Science. 268:423–426. 1995. View Article : Google Scholar : PubMed/NCBI
11	Noma A: ATP-regulated K⁺ channels in cardiac muscle. Nature. 305:147–148. 1983. View Article : Google Scholar : PubMed/NCBI
12	Quayle JM, Nelson MT and Standen NB: ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev. 77:1165–1232. 1997. View Article : Google Scholar : PubMed/NCBI
13	Sakura H, Ammälä C, Smith PA, Gribble FM and Ashcroft FM: Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett. 377:338–344. 1995. View Article : Google Scholar : PubMed/NCBI
14	Trube G, Rorsman P and Ohno-Shosaku T: Opposite effects of tolbutamide and diazoxide on the ATP-dependent K⁺ channel in mouse pancreatic beta-cells. Pflugers Arch. 407:493–499. 1986. View Article : Google Scholar : PubMed/NCBI
15	Sturgess NC, Ashford ML, Cook DL and Hales CN: The sulphonylurea receptor may be an ATP-sensitive potassium channel. Lancet. 2:474–475. 1985. View Article : Google Scholar : PubMed/NCBI
16	Kasikcioglu HA and Cam N: A review of levosimendan in the treatment of heart failure. Vasc Health Risk Manag. 2:389–400. 2006. View Article : Google Scholar : PubMed/NCBI
17	Downey JM and Cohen MV: Do mitochondrial KATP channels serve as triggers rather than end-effectors of ischemic preconditioning's protection? Basic Res Cardiol. 95:272–274. 2000. View Article : Google Scholar : PubMed/NCBI
18	Malhi H, Irani AN, Rajvanshi P, Suadicani SO, Spray DC, McDonald TV and Gupta S: KATP channels regulate mitogenically induced proliferation in primary rat hepatocytes and human liver cell lines. Implications for liver growth control and potential therapeutic targeting. J Biol Chem. 275:26050–26057. 2000. View Article : Google Scholar : PubMed/NCBI
19	Monen SH, Schmidt PH and Wondergem R: Membrane potassium channels and human bladder tumor cells. I. Electrical properties. J Membr Biol. 161:247–256. 1998. View Article : Google Scholar : PubMed/NCBI
20	Qian X, Li J, Ding J, Wang Z, Duan L and Hu G: Glibenclamide exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803. Biochem Pharmacol. 76:1705–1715. 2008. View Article : Google Scholar : PubMed/NCBI
21	Huang L, Li B, Li W, Guo H and Zou F: ATP-sensitive potassium channels control glioma cells proliferation by regulating ERK activity. Carcinogenesis. 30:737–744. 2009. View Article : Google Scholar : PubMed/NCBI
22	Wondergem R, Cregan M, Strickler L, Miller R and Suttles J: Membrane potassium channels and human bladder tumor cells: II. Growth properties. J Membr Biol. 161:257–262. 1998. View Article : Google Scholar : PubMed/NCBI
23	Abdul M and Hoosein N: Expression and activity of potassium ion channels in human prostate cancer. Cancer Lett. 186:99–105. 2002. View Article : Google Scholar : PubMed/NCBI
24	Farias LM, Ocaña DB, Díaz L, Larrea F, Avila-Chávez E, Cadena A, Hinojosa LM, Lara G, Villanueva LA, Vargas C, et al: Ether a go-go potassium channels as human cervical cancer markers. Cancer Res. 64:6996–7001. 2004. View Article : Google Scholar : PubMed/NCBI
25	Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 105:103–104. 2009. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Payen L, Delugin L, Courtois A, Trinquart Y, Guillouzo A and Fardel O: The sulphonylurea glibenclamide inhibits multidrug resistance protein (MRP1) activity in human lung cancer cells. Br J Pharmacol. 132:778–784. 2001. View Article : Google Scholar : PubMed/NCBI
28	Borst P, Evers R, Kool M and Wijnholds J: The multidrug resistance protein family. Biochim Biophys Acta. 1461:347–357. 1999. View Article : Google Scholar : PubMed/NCBI
29	Lautier D, Canitrot Y, Deeley RG and Cole SP: Multidrug resistance mediated by the multidrug resistance protein (MRP) gene. Biochem Pharmacol. 52:967–977. 1996. View Article : Google Scholar : PubMed/NCBI
30	Sheppard DN and Robinson KA: Mechanism of glibenclamide inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in a murine cell line. J Physiol. 503:333–346. 1997. View Article : Google Scholar : PubMed/NCBI
31	Kim JA, Kang YS, Lee SH, Lee EH, Yoo BH and Lee YS: Glibenclamide induces apoptosis through inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels and intracellular Ca(2+) release in HepG2 human hepatoblastoma cells. Biochem Biophys Res Commun. 261:682–688. 1999. View Article : Google Scholar : PubMed/NCBI
32	Sheppard DN and Welsh MJ: Effect of ATP-sensitive K⁺ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents. J Gen Physiol. 100:573–591. 1992. View Article : Google Scholar : PubMed/NCBI
33	Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF and Meier PJ: The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem. 273:10046–10050. 1998. View Article : Google Scholar : PubMed/NCBI
34	Stieger B, Fattinger K, Madon J, Kullak-Ublick GA and Meier PJ: Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology. 118:422–430. 2000. View Article : Google Scholar : PubMed/NCBI
35	Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I and Gottesman MM: Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol. 39:361–398. 1999. View Article : Google Scholar : PubMed/NCBI
36	Golstein PE, Boom A, van Geffel J, Jacobs P, Masereel B and Beauwens R: P-glycoprotein inhibition by glibenclamide and related compounds. Pflugers Arch. 437:652–660. 1999. View Article : Google Scholar : PubMed/NCBI
37	Peng X, Wu Z, Yu L, Li J, Xu W, Chan HC, Zhang Y and Hu L: Overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) is associated with human cervical cancer malignancy, progression and prognosis. Gynecol Oncol. 125:470–476. 2012. View Article : Google Scholar : PubMed/NCBI
38	Núñez M, Medina V, Cricco G, Croci M, Cocca C, Rivera E, Bergoc R and Martín G: Glibenclamide inhibits cell growth by inducing G0/G1 arrest in the human breast cancer cell line MDA-MB-231. BMC Pharmacol Toxicol. 14:62013. View Article : Google Scholar : PubMed/NCBI
39	Artym VV and Petty HR: Molecular proximity of Kv1.3 voltage-gated potassium channels and beta(1)-integrins on the plasma membrane of melanoma cells: Effects of cell adherence and channel blockers. J Gen Physiol. 120:29–37. 2002. View Article : Google Scholar : PubMed/NCBI
40	Agarwal JR, Griesinger F, Stühmer W and Pardo LA: The potassium channel Ether à go-go is a novel prognostic factor with functional relevance in acute myeloid leukemia. Mol Cancer. 9:182010. View Article : Google Scholar : PubMed/NCBI
41	Afrasiabi E, Hietamäki M, Viitanen T, Sukumaran P, Bergelin N and Törnquist K: Expression and significance of HERG (KCNH2) potassium channels in the regulation of MDA-MB-435S melanoma cell proliferation and migration. Cell Signal. 22:57–64. 2010. View Article : Google Scholar : PubMed/NCBI
42	Pillozzi S, Brizzi MF, Bernabei PA, Bartolozzi B, Caporale R, Basile V, Boddi V, Pegoraro L, Becchetti A and Arcangeli A: VEGFR-1 (FLT-1), beta1 integrin, and hERG K⁺ channel for a macromolecular signaling complex in acute myeloid leukemia: Role in cell migration and clinical outcome. Blood. 110:1238–1250. 2007. View Article : Google Scholar : PubMed/NCBI
43	Cherubini A, Hofmann G, Pillozzi S, Guasti L, Crociani O, Cilia E, Di Stefano P, Degani S, Balzi M, Olivotto M, et al: Human ether-a-go-go-related gene 1 channels are physically linked to beta1 integrins and modulate adhesion-dependent signaling. Mol Biol Cell. 16:2972–2983. 2005. View Article : Google Scholar : PubMed/NCBI
44	Lastraioli E, Guasti L, Crociani O, Polvani S, Hofmann G, Witchel H, Bencini L, Calistri M, Messerini L, Scatizzi M, et al: herg1 gene and HERG1 protein are overexpressed in colorectal cancers and regulate cell invasion of tumor cells. Cancer Res. 64:606–611. 2004. View Article : Google Scholar : PubMed/NCBI
45	Guo Z, Liu J, Zhang L, Su B, Xing Y, He Q, Ci W, Li X and Zhou L: KCNJ1 inhibits tumor proliferation and metastasis and is a prognostic factor in clear cell renal cell carcinoma. Tumour Biol. 36:1251–1259. 2015. View Article : Google Scholar : PubMed/NCBI
46	Veeravalli KK, Ponnala S, Chetty C, Tsung AJ, Gujrati M and Rao JS: Integrin α9β1-mediated cell migration in glioblastoma via SSAT and Kir4.2 potassium channel pathway. Cell Signal. 24:272–281. 2012. View Article : Google Scholar : PubMed/NCBI
47	Kraft R, Krause P, Jung S, Basrai D, Liebmann L, Bolz J and Patt S: BK channel openers inhibit migration of human glioma cells. Pflugers Arch. 446:248–255. 2003. View Article : Google Scholar : PubMed/NCBI
48	Weaver AK, Bomben VC and Sontheimer H: Expression and function of calcium-activated potassium channels in human glioma cells. Glia. 54:223–233. 2006. View Article : Google Scholar : PubMed/NCBI
49	Sciaccaluga M, Fioretti B, Catacuzzeno L, Pagani F, Bertollini C, Rosito M, Catalano M, D'Alessandro G, Santoro A, Cantore G, et al: CXCL12-induced glioblastoma cell migration requires intermediate conductance Ca²⁺-activated K⁺ channel activity. Am J Physiol Cell Physiol. 299:C175–C184. 2010. View Article : Google Scholar : PubMed/NCBI
50	Cuddapah VA, Turner KL, Seifert S and Sontheimer H: Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3. J Neurosci. 33:1427–1440. 2013. View Article : Google Scholar : PubMed/NCBI
51	Chantôme A, Potier-Cartereau M, Clarysse L, Fromont G, Marionneau-Lambot S, Guéguinou M, Pagès JC, Collin C, Oullier T, Girault A, et al: Pivotal role of the lipid Raft SK3-Orai1 complex in human cancer cell migration and bone metastases. Cancer Res. 73:4852–4861. 2013. View Article : Google Scholar : PubMed/NCBI
52	Liu X and Chang Y, Reinhart PH, Sontheimer H and Chang Y: Cloning and characterization of glioma BK, a Novel BK Channel isoform highly expressed in human glioma cells. J Neurosci. 22:1840–1849. 2002. View Article : Google Scholar : PubMed/NCBI