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Published in: Annals of Surgical Oncology 6/2011

01-06-2011 | Translational Research and Biomarkers

Salinomycin Selectively Targets ‘CD133+’ Cell Subpopulations and Decreases Malignant Traits in Colorectal Cancer Lines

Authors: Tao-Tao Dong, Hou-Min Zhou, Lin-Lin Wang, Bo Feng, Bo Lv, Min-Hua Zheng

Published in: Annals of Surgical Oncology | Issue 6/2011

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Abstract

Background

Cancer stem-like cells (CSCs) in colorectal cancers (CRC) may account for the failure of treatments because they are resistant to many current anticancer therapies. Salinomycin, a potassium ionophore, was recently identified as a selective inhibitor of breast CSCs.

Methods

The human CRC cell lines HT29 and SW480 were treated with salinomycin and oxaliplatin. Cell viability was determined with cell counting kit 8. Fraction of CD133+ cell subpopulations was assessed by Flow Cytometric analysis. Clonogenecity and migration were determined with soft agar and Boyden chamber assays. Molecular changes were assessed by immunofluorescence staining, RT-PCR, and Western blot analysis.

Results

We report that salinomycin reduces the proportion of CD133+ subpopulations in human CRC HT29 and SW480 cells. Furthermore, salinomycin treatment decreases colony-forming ability and cell motility in HT29 cells. Moreover, salinomycin downregulates the expression of vimentin and induces the E-cadherin expression in HT29 cells.

Conclusions

This study demonstrates the ability of salinomycin to selectively target “CD133+” cell subpopulations and decrease the malignant traits in colorectal cancer lines.
Literature
1.
go back to reference O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445(7123):106–10.PubMedCrossRef O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445(7123):106–10.PubMedCrossRef
2.
go back to reference Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.PubMedCrossRef Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.PubMedCrossRef
3.
go back to reference Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 2007;104(24):10158–63.PubMedCrossRef Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 2007;104(24):10158–63.PubMedCrossRef
4.
go back to reference Ieta K, Tanaka F, Haraguchi N, Kita Y, Sakashita H, Mimori K, Matsumoto T, Inoue H, Kuwano H, Mori M. Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol. 2008;15(2):638–48.PubMedCrossRef Ieta K, Tanaka F, Haraguchi N, Kita Y, Sakashita H, Mimori K, Matsumoto T, Inoue H, Kuwano H, Mori M. Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol. 2008;15(2):638–48.PubMedCrossRef
5.
go back to reference Haraguchi N, Ohkuma M, Sakashita H, Matsuzaki S, Tanaka F, Mimori K, Kamohara Y, Inoue H, Mori M. CD133+ CD44+ population efficiently enriches colon cancer initiating cells. Ann Surg Oncol. 2008;15(10):2927–33.PubMedCrossRef Haraguchi N, Ohkuma M, Sakashita H, Matsuzaki S, Tanaka F, Mimori K, Kamohara Y, Inoue H, Mori M. CD133+ CD44+ population efficiently enriches colon cancer initiating cells. Ann Surg Oncol. 2008;15(10):2927–33.PubMedCrossRef
6.
go back to reference Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.PubMedCrossRef Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.PubMedCrossRef
7.
go back to reference Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–84.PubMedCrossRef Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–84.PubMedCrossRef
8.
go back to reference Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458(7239):780–3.PubMedCrossRef Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458(7239):780–3.PubMedCrossRef
9.
go back to reference Diehn M, Clarke MF. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. J Natl Cancer Inst. 2006;98(24):1755–7.PubMedCrossRef Diehn M, Clarke MF. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. J Natl Cancer Inst. 2006;98(24):1755–7.PubMedCrossRef
10.
go back to reference Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol. 2008;26(17):2839–45.PubMedCrossRef Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol. 2008;26(17):2839–45.PubMedCrossRef
11.
go back to reference Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1(4):389–402.PubMedCrossRef Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1(4):389–402.PubMedCrossRef
12.
go back to reference Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–59.PubMedCrossRef Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–59.PubMedCrossRef
13.
go back to reference Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.PubMedCrossRef Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.PubMedCrossRef
14.
go back to reference Yang AD, Fan F, Camp ER, van Buren G, Liu W, Somcio R, Gray MJ, Cheng H, Hoff PM, Ellis LM. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006;12(14 Pt 1):4147–53.PubMedCrossRef Yang AD, Fan F, Camp ER, van Buren G, Liu W, Somcio R, Gray MJ, Cheng H, Hoff PM, Ellis LM. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006;12(14 Pt 1):4147–53.PubMedCrossRef
15.
go back to reference Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, Waldvogel B, Vannier C, Darling D, zur Hausen A, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009;11(12):1487–95.PubMedCrossRef Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, Waldvogel B, Vannier C, Darling D, zur Hausen A, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009;11(12):1487–95.PubMedCrossRef
16.
go back to reference Neuzil J, Stantic M, Zobalova R, Chladova J, Wang X, Prochazka L, Dong L, Andera L, Ralph SJ. Tumour-initiating cells vs. cancer ‘stem’ cells and CD133: what’s in the name? Biochem Biophys Res Commun. 2007;355(4):855–9.PubMedCrossRef Neuzil J, Stantic M, Zobalova R, Chladova J, Wang X, Prochazka L, Dong L, Andera L, Ralph SJ. Tumour-initiating cells vs. cancer ‘stem’ cells and CD133: what’s in the name? Biochem Biophys Res Commun. 2007;355(4):855–9.PubMedCrossRef
17.
go back to reference Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68(10):3645–54.PubMedCrossRef Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68(10):3645–54.PubMedCrossRef
18.
go back to reference Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.PubMedCrossRef Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.PubMedCrossRef
19.
go back to reference Ong CW, Kim LG, Kong HH, Low LY, Iacopetta B, Soong R, Salto-Tellez M. CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol. 23(3):450–7. Ong CW, Kim LG, Kong HH, Low LY, Iacopetta B, Soong R, Salto-Tellez M. CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol. 23(3):450–7.
20.
go back to reference Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C, Kusunoki M. Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol. 2009;16(12):3488–98.PubMedCrossRef Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C, Kusunoki M. Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol. 2009;16(12):3488–98.PubMedCrossRef
21.
go back to reference Artells R, Moreno I, Diaz T, Martinez F, Gel B, Navarro A, Ibeas R, Moreno J, Monzo M. Tumour CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patients. Eur J Cancer. 2010;46(3):642–9. Artells R, Moreno I, Diaz T, Martinez F, Gel B, Navarro A, Ibeas R, Moreno J, Monzo M. Tumour CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patients. Eur J Cancer. 2010;46(3):642–9.
22.
go back to reference Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB. The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem. 2000;275(8):5512–20.PubMedCrossRef Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB. The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem. 2000;275(8):5512–20.PubMedCrossRef
23.
go back to reference Giebel B, Corbeil D, Beckmann J, Hohn J, Freund D, Giesen K, Fischer J, Kogler G, Wernet P. Segregation of lipid raft markers including CD133 in polarized human hematopoietic stem and progenitor cells. Blood. 2004;104(8):2332–8.PubMedCrossRef Giebel B, Corbeil D, Beckmann J, Hohn J, Freund D, Giesen K, Fischer J, Kogler G, Wernet P. Segregation of lipid raft markers including CD133 in polarized human hematopoietic stem and progenitor cells. Blood. 2004;104(8):2332–8.PubMedCrossRef
24.
go back to reference Elsaba TM, Martinez-Pomares L, Robins AR, Crook S, Seth R, Jackson D, McCart A, Silver AR, Tomlinson IP, Ilyas M. The stem cell marker CD133 associates with enhanced colony formation and cell motility in colorectal cancer. PLoS One. 2010;5(5):e10714.PubMedCrossRef Elsaba TM, Martinez-Pomares L, Robins AR, Crook S, Seth R, Jackson D, McCart A, Silver AR, Tomlinson IP, Ilyas M. The stem cell marker CD133 associates with enhanced colony formation and cell motility in colorectal cancer. PLoS One. 2010;5(5):e10714.PubMedCrossRef
25.
go back to reference Rappa G, Fodstad O, Lorico A. The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells. 2008;26(12):3008–17.CrossRef Rappa G, Fodstad O, Lorico A. The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells. 2008;26(12):3008–17.CrossRef
26.
go back to reference Fuchs D, Heinold A, Opelz G, Daniel V, Naujokat C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem Biophys Res Commun. 2009;390(3):743–9.PubMedCrossRef Fuchs D, Heinold A, Opelz G, Daniel V, Naujokat C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem Biophys Res Commun. 2009;390(3):743–9.PubMedCrossRef
27.
go back to reference Riccioni R, Dupuis ML, Bernabei M, Petrucci E, Pasquini L, Mariani G, Cianfriglia M, Testa U. The cancer stem cell selective inhibitor salinomycin is a p-glycoprotein inhibitor. Blood Cells Mol Dis. 2010;45(1):86–92. Riccioni R, Dupuis ML, Bernabei M, Petrucci E, Pasquini L, Mariani G, Cianfriglia M, Testa U. The cancer stem cell selective inhibitor salinomycin is a p-glycoprotein inhibitor. Blood Cells Mol Dis. 2010;45(1):86–92.
28.
go back to reference Fuchs D, Daniel V, Sadeghi M, Opelz G, Naujokat C. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells. Biochem Biophys Res Commun. 2010;394(4):1098–104. Fuchs D, Daniel V, Sadeghi M, Opelz G, Naujokat C. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells. Biochem Biophys Res Commun. 2010;394(4):1098–104.
29.
go back to reference Yvore P, Raynaud JP, Conan L, Naciri M. Evaluation of the efficacy of salinomycin in the control of coccidiosis in chicks. Poult Sci. 1980;59(11):2412–6.PubMed Yvore P, Raynaud JP, Conan L, Naciri M. Evaluation of the efficacy of salinomycin in the control of coccidiosis in chicks. Poult Sci. 1980;59(11):2412–6.PubMed
30.
go back to reference Callaway TR, Edrington TS, Rychlik JL, Genovese KJ, Poole TL, Jung YS, Bischoff KM, Anderson RC, Nisbet DJ. Ionophores: their use as ruminant growth promotants and impact on food safety. Curr Issues Intest Microbiol. 2003;4(2):43–51.PubMed Callaway TR, Edrington TS, Rychlik JL, Genovese KJ, Poole TL, Jung YS, Bischoff KM, Anderson RC, Nisbet DJ. Ionophores: their use as ruminant growth promotants and impact on food safety. Curr Issues Intest Microbiol. 2003;4(2):43–51.PubMed
31.
go back to reference Li Y, Fang J, Wu S, Ma K, Li H, Yan X, Dong F. Identification and quantification of salinomycin in intoxicated human plasma by liquid chromatography-electrospray tandem mass spectrometry. Anal Bioanal Chem. 2010;398(2):955–61. Li Y, Fang J, Wu S, Ma K, Li H, Yan X, Dong F. Identification and quantification of salinomycin in intoxicated human plasma by liquid chromatography-electrospray tandem mass spectrometry. Anal Bioanal Chem. 2010;398(2):955–61.
32.
go back to reference Story P, Doube A. A case of human poisoning by salinomycin, an agricultural antibiotic. N Z Med J. 2004;117(1190):U799.PubMed Story P, Doube A. A case of human poisoning by salinomycin, an agricultural antibiotic. N Z Med J. 2004;117(1190):U799.PubMed
33.
go back to reference Kojima M, Ishii G, Atsumi N, Nishizawa Y, Saito N, Ochiai A. CD133 expression in rectal cancer after preoperative chemoradiotherapy. Cancer Sci. 2010;101(4):906–12. Kojima M, Ishii G, Atsumi N, Nishizawa Y, Saito N, Ochiai A. CD133 expression in rectal cancer after preoperative chemoradiotherapy. Cancer Sci. 2010;101(4):906–12.
35.
go back to reference Weinberg RA. The rational treatment of cancer. In: Zayatz E, editor. The biology of cancer. New York: Garland Science; 2007. p. 787–94. Weinberg RA. The rational treatment of cancer. In: Zayatz E, editor. The biology of cancer. New York: Garland Science; 2007. p. 787–94.
Metadata
Title
Salinomycin Selectively Targets ‘CD133+’ Cell Subpopulations and Decreases Malignant Traits in Colorectal Cancer Lines
Authors
Tao-Tao Dong
Hou-Min Zhou
Lin-Lin Wang
Bo Feng
Bo Lv
Min-Hua Zheng
Publication date
01-06-2011
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 6/2011
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-011-1561-2

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