An inhibitor of K+ channels modulates human endometrial tumor-initiating cells

Cancer Cell International

Victoria P Korovkina³  Douglas R Spitz²  Kimberly K Leslie²  Nukhet Aykin-Burns¹  Brandon M Schickling³ 

[1] Free Radical and Radiation Biology Program, University of Iowa, B180 Med Labs, Iowa City, IA 52242, USA;Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242, USA;Department of Obstetrics and Gynecology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA

关键词: tumor initiating cells;    cancer stem cells;    potassium channels;    endometrial cancer;   

Others  :  795487
DOI  :  10.1186/1475-2867-11-25

 received in 2011-06-29, accepted in 2011-08-02,  发布年份 2011

【 摘 要 】

Background

Many potassium ion (K⁺) channels function as oncogenes to sustain growth of solid tumors, but their role in cancer progression is not well understood. Emerging evidence suggests that the early progenitor cancer cell subpopulation, termed tumor initiating cells (TIC), are critical to cancer progression.

Results

A non-selective antagonist of multiple types of K⁺ channels, tetraethylammonium (TEA), was found to suppress colony formation in endometrial cancer cells via inhibition of putative TIC. The data also indicated that withdrawal of TEA results in a significant enhancement of tumorigenesis. When the TIC-enriched subpopulation was isolated from the endometrial cancer cells, TEA was also found to inhibit growth in vitro.

Conclusions

These studies suggest that the activity of potassium channels significantly contributes to the progression of endometrial tumors, and the antagonists of potassium channels are candidate anti-cancer drugs to specifically target tumor initiating cells in endometrial cancer therapy.

【 授权许可】

   
2011 Schickling et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Stuhmer W, Pardo LA: K(+) channels as therapeutic targets in oncology. Future Med Chem 2010, 2:745-755.
• [2]Asher V, Sowter H, Shaw R, Bali A, Khan R: Eag and HERG potassium channels as novel therapeutic targets in cancer. World J Surg Oncol 2010, 8:113. BioMed Central Full Text
• [3]Ernest NJ, Logsdon NJ, McFerrin MB, Sontheimer H, Spiller SE: Biophysical properties of human medulloblastoma cells. J Membr Biol 2010, 237:59-69.
• [4]Bielanska J, Hernandez-Losa J, Perez-Verdaguer M, Moline T, Somoza R, Ramon YCS, Condom E, Ferreres JC, Felipe A: Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human cancer. Curr Cancer Drug Targets 2009, 9:904-914.
• [5]Wondergem R, Bartley JW: Menthol increases human glioblastoma intracellular Ca2+, BK channel activity and cell migration. J Biomed Sci 2009, 16:90. BioMed Central Full Text
• [6]Khaitan D, Sankpal UT, Weksler B, Meister EA, Romero IA, Couraud PO, Ningaraj NS: Role of KCNMA1 gene in breast cancer invasion and metastasis to brain. BMC Cancer 2009, 9:258. BioMed Central Full Text
• [7]Brevet M, Haren N, Sevestre H, Merviel P, Ouadid-Ahidouch H: DNA methylation of K(v)1.3 potassium channel gene promoter is associated with poorly differentiated breast adenocarcinoma. Cell Physiol Biochem 2009, 24:25-32.
• [8]Nakamura M, Kyo S, Zhang B, Zhang X, Mizumoto Y, Takakura M, Maida Y, Mori N, Hashimoto M, Ohno S, Inoue M: Prognostic impact of CD133 expression as a tumor-initiating cell marker in endometrial cancer. Hum Pathol 2010, 41:1516-1529.
• [9]Chantome A, Girault A, Potier M, Collin C, Vaudin P, Pages JC, Vandier C, Joulin V: KCa2.3 channel-dependent hyperpolarization increases melanoma cell motility. Exp Cell Res 2009, 315:3620-3630.
• [10]Blackiston DJ, McLaughlin KA, Levin M: Bioelectric controls of cell proliferation: ion channels, membrane voltage and the cell cycle. Cell Cycle 2009, 8:3519-3528.
• [11]Sciaccaluga M, Fioretti B, Catacuzzeno L, Pagani F, Bertollini C, Rosito M, Catalano M, D'Alessandro G, Santoro A, Cantore G, Ragozzino D, Castigli E, Franciolini F, Limatola C: CXCL12-induced glioblastoma cell migration requires intermediate conductance Ca2+-activated K+ channel activity. Am J Physiol Cell Physiol 2010, 299:C175-184.
• [12]Becchetti A, Arcangeli A: Integrins and ion channels in cell migration: implications for neuronal development, wound healing and metastatic spread. Adv Exp Med Biol 2010, 674:107-123.
• [13]Haren N, Khorsi H, Faouzi M, Ahidouch A, Sevestre H, Ouadid-Ahidouch H: Intermediate conductance Ca2+ activated K+ channels are expressed and functional in breast adenocarcinomas: correlation with tumour grade and metastasis status. Histol Histopathol 2010, 25:1247-1255.
• [14]Lee I, Park C, Kang WK: Knockdown of inwardly rectifying potassium channel Kir2.2 suppresses tumorigenesis by inducing reactive oxygen species-mediated cellular senescence. Mol Cancer Ther 2010, 9:2951-2959.
• [15]Fortunato P, Pillozzi S, Tamburini A, Pollazzi L, Franchi A, La Torre A, Arcangeli A: Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway. BMC Cancer 2010, 10:504. BioMed Central Full Text
• [16]Tajima N, Itokazu Y, Korpi ER, Somerharju P, Kakela R: Activity of BK(Ca) channel is modulated by membrane cholesterol content and association with Na+/K+-ATPase in human melanoma IGR39 cells. J Biol Chem 2011, 286:5624-5638.
• [17]Asher V, Khan R, Warren A, Shaw R, Schalkwyk GV, Bali A, Sowter HM: The Eag potassium channel as a new prognostic marker in ovarian cancer. Diagn Pathol 2010, 5:78. BioMed Central Full Text
• [18]Jelassi B, Chantome A, Alcaraz-Perez F, Baroja-Mazo A, Cayuela ML, Pelegrin P, Surprenant A, Roger S: P2X(7) receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness. Oncogene 2011, 30:2108-2122.
• [19]Lallet-Daher H, Roudbaraki M, Bavencoffe A, Mariot P, Gackiere F, Bidaux G, Urbain R, Gosset P, Delcourt P, Fleurisse L, Slomianny C, Dewailly E, Mauroy B, Bonnal JL, Skryma R, Prevarskaya N: Intermediate-conductance Ca2+-activated K+ channels (IKCa1) regulate human prostate cancer cell proliferation through a close control of calcium entry. Oncogene 2009, 28:1792-1806.
• [20]Asher V, Warren A, Shaw R, Sowter H, Bali A, Khan R: The role of Eag and HERG channels in cell proliferation and apoptotic cell death in SK-OV-3 ovarian cancer cell line. Cancer Cell Int 2011, 11:6. BioMed Central Full Text
• [21]Kim HJ, Jang SH, Jeong YA, Ryu PD, Kim DY, Lee SY: Involvement of Kv4.1 K(+) channels in gastric cancer cell proliferation. Biol Pharm Bull 2010, 33:1754-1757.
• [22]Biderman B, Marakhonov A, Skoblov M, Birerdinc A, Nohelty E, Page S, Khomenkov V, Chandhoke V, Sudarikov A, Nikitin E, Baranova A: Inhibition of potassium currents as a pharmacologic target for investigation in chronic lymphocytic leukemia. Drug News Perspect 2010, 23:625-631.
• [23]Pillozzi S, Masselli M, De Lorenzo E, Accordi B, Cilia E, Crociani O, Amedei A, Veltroni M, D'Amico M, Basso G, Becchetti A, Campana D, Arcangeli A: Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers. Blood 2011, 117:902-914.
• [24]Agarwal JR, Griesinger F, Stuhmer W, Pardo LA: The potassium channel Ether a go-go is a novel prognostic factor with functional relevance in acute myeloid leukemia. Mol Cancer 2010, 9:18. BioMed Central Full Text
• [25]Jang SH, Kang KS, Ryu PD, Lee SY: Kv1.3 voltage-gated K(+) channel subunit as a potential diagnostic marker and therapeutic target for breast cancer. BMB Rep 2009, 42:535-539.
• [26]Dolderer JH, Schuldes H, Bockhorn H, Altmannsberger M, Lambers C, von Zabern D, Jonas D, Schwegler H, Linke R, Schroder UH: HERG1 gene expression as a specific tumor marker in colorectal tissues. Eur J Surg Oncol 2010, 36:72-77.
• [27]Teng IW, Hou PC, Lee KD, Chu PY, Yeh KT, Jin VX, Tseng MJ, Tsai SJ, Chang YSD, Wu CS, Sun HS, Tsai KD, Jeng LB, Nephew KP, Huang TH, Hsiao SH, Leu YW: Targeted methylation of two tumor suppressor genes is sufficient to transform mesenchymal stem cells into cancer stem/initiating cells. Cancer Res 2011.
• [28]Kano M, Tsukahara T, Emori M, Murase M, Torigoe T, Kawaguchi S, Wada T, Yamashita T, Sato N: Autologous CTL response against cancer stem-like cells/cancer-initiating cells of bone malignant fibrous histiocytoma. Cancer Sci 2011.
• [29]Deleyrolle LP, Harding A, Cato K, Siebzehnrubl FA, Rahman M, Azari H, Olson S, Gabrielli B, Osborne G, Vescovi A, Reynolds BA: Evidence for label-retaining tumour-initiating cells in human glioblastoma. Brain 2011, 134:1331-1343.
• [30]Albitar L, Pickett G, Morgan M, Davies S, Leslie KK: Models representing type I and type II human endometrial cancers: Ishikawa H and Hec50co cells. Gynecol Oncol 2007, 106:52-64.
• [31]Cherubini A, Taddei GL, Crociani O, Paglierani M, Buccoliero AM, Fontana L, Noci I, Borri P, Borrani E, Giachi M, Becchetti A, Rosati B, Wanke E, Olivotto M, Arcangeli A: HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium. Br J Cancer 2000, 83:1722-1729.
• [32]Wang ZH, Shen B, Yao HL, Jia YC, Ren J, Feng YJ, Wang YZ: Blockage of intermediate-conductance-Ca(2+) -activated K(+) channels inhibits progression of human endometrial cancer. Oncogene 2007, 26:5107-5114.
• [33]Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, Bernard L, Viale G, Pelicci PG, Di Fiore PP: Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 2010, 140:62-73.
• [34]Heerma van Voss MR, van der Groep P, Bart J, van der Wall E, van Diest PJ: Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer. Cell Oncol (Dordr) 2011, 34:3-10.
• [35]Rahadiani N, Ikeda J, Mamat S, Matsuzaki S, Ueda Y, Umehara R, Tian T, Wang Y, Enomoto T, Kimura T, Aozasa K, Morii E: Expression of aldehyde dehydrogenase 1 (ALDH1) in endometrioid adenocarcinoma and its clinical implications. Cancer Sci 2011, 102:903-908.
• [36]Kusumbe AP, Bapat SA: Cancer stem cells and aneuploid populations within developing tumors are the major determinants of tumor dormancy. Cancer Res 2009, 69:9245-9253.
• [37]Potier M, Chantome A, Joulin V, Girault A, Roger S, Besson P, Jourdan ML, LeGuennec JY, Bougnoux P, Vandier C: The SK3/K(Ca)2.3 potassium channel is a new cellular target for edelfosine. Br J Pharmacol 2011, 162:464-479.