Establishment and characterization of multi-drug resistant, prostate carcinoma-initiating stem-like cells from human prostate cancer cell lines 22RV1
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Multi-drug resistance is an important element which leads to ineffectiveness of chemotherapeutics. To identify subpopulations of cancerous prostate cells with mutli-drug resistance and cancer stem-cell properties has recently become a major research interest. We identified a subpopulation from the prostate cancer cell line 22RV1, which have high surface expression of both CD117 and ABCG2. We found this subpopulation of cells termed CD117+/ABCG2+ also overexpress stem cells markers such as Nanog, Oct4, Sox2, Nestin, and CD133. These cells are highly prolific and are also resistant to treatment with a variety of chemotherapeutics such as casplatin, paclitaxel, adriamycin, and methotrexate. In addition, CD117+/ABCG2+ cells can readily establish tumors in vivo in a relatively short time. To investigate the mechanism of aggressive tumor growth and drug resistance, we examined the CpG islands on the ABCG2 promoter of CD117+/ABCG2+ cells and found they were remarkably hypomethylated. Furthermore, chromatin immunoprecipitation assays revealed high levels of both histone 3 acetylation and H3K4 trimethylation at the CpG islands on the ABCG2 promoter. Our these data suggest that CD117+/ABCG2+ cells could be reliably sorted from the human prostate cancer cell line 22RV1, and represent a valuable model for studying cancer cell physiology and multi-drug resistance. Furthermore, identification and study of these cells could have a profound impact on selection of individual treatment strategies, clinical outcome, and the design or selection of the next generation of chemotherapeutic agents.
KeywordsCarcinoma-initiating stem-like cells ABCG2 Multidrugs resistant Epigenetic modification Cell models
This work was supported by grant from the Shanghai Municipal Health Bureau Fund for Young Scholars (No. 2008Y002) and Medicine-Engineering Unite Fund for Shanghai Jiaotong University (No. YG2009MS47) and Shanghai Committee Medical Science Foundation of China (No. 10411967100) to Te Liu. And this work was supported by a grant from the National High Technology Research and Development Program of China (863 Program) (No.2008AA101001) and Science and Technology Department of Shanghai Research Fund (No.07DZ19063-2) to Zhixue Liu. We thank Dr Jun Liu (Rutgers University) for discussion and proofreading the manuscript.
- 15.Monzani E, Facchetti F, Galmozzi E, Corsini E, Benetti A, Cavazzin C, Gritti A, Piccinini A, Porro D, Santinami M, Invernici G, Parati E, Alessandri G, La Porta CA (2007) Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer 43:935–946CrossRefPubMedGoogle Scholar
- 19.Chen Z, Liu F, Ren Q, Zhao Q, Ren H, Lu S, Zhang L, Han Z (2010) Suppression of ABCG2 inhibits cancer cell proliferation. Int J Cancer 126:841–851Google Scholar
- 25.Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT, Donahoe PK (2006) Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. Proc Natl Acad Sci USA 103:11154–11159CrossRefPubMedGoogle Scholar
- 30.Xi S, Geiman TM, Briones V, Tao YG, Xu H, Muegge K (2009) Lsh participates in DNA methylation and silencing of stem cell genes. Stem Cells 26:2691–2702Google Scholar
- 34.Kumamoto H and Ohki K (2010) Detection of CD133, Bmi-1, and ABCG2 in ameloblastic tumors. J Oral Pathol Med 39:87–93Google Scholar
- 45.Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125:301–313CrossRefPubMedGoogle Scholar
- 46.Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349–353CrossRefPubMedGoogle Scholar