The inhibitory effect of salinomycin on the proliferation, migration and invasion of human endometrial cancer stem-like cells

• Published in: Gynecologic oncology 2013-06, Vol.129 (3), p.598-605
• Main Authors: Kusunoki, Soshi, Kato, Kiyoko, Tabu, Kouichi, Inagaki, Tetsunori, Okabe, Hitomi, Kaneda, Hiroshi, Suga, Shin, Terao, Yasuhisa, Taga, Tetsuya, Takeda, Satoru
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; bcl-2-Associated X Protein - biosynthesis; Cancer stem cell; Cell Growth Processes - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Endometrium - drug effects; Endometrium - pathology; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Female; Fibronectin; Fibronectins - biosynthesis; Hematology, Oncology and Palliative Medicine; Humans; Neoplasm Invasiveness; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Obstetrics and Gynecology; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Pyrans - pharmacology; Rats; Salinomycin; Side-population cells; Signal Transduction - drug effects; Wnt Proteins - metabolism
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2013.03.005

Abstract Goals We previously demonstrated that side-population (SP) cells in human endometrial cancer cells (Hec1 cells) and in rat endometrial cells expressing oncogenic human K-Ras protein (RK12V cells) have features of cancer stem cells (CSCs). Hec1-SP cells showed enhanced migration and the potential to differentiate into the mesenchymal cell lineage. In this study, we analyzed the association of the epithelial–mesenchymal transition (EMT) with the properties of these endometrial CSCs. We also assessed the effects of salinomycin (a compound with EMT-specific toxicity) on the proliferative capacity, migration and invasiveness of these endometrial CSCs using Hec1-SP cells. Method We performed microarray expression analysis to screen for up-regulated genes in CSCs using a set of RK12V-SP cells and -non-SP(NSP) cells and used the Metacore package to identify the Gene GO pathway MAPs involved in the up-regulated genes. To analyze their association with EMT, the expression of several EMT associated genes in Hec1-SP cells was investigated by real time PCR and compared with that in Hec1-NSP cells. We assessed the expression of BAX , BCL2 , LEF1 , cyclinD and fibronectin by real time PCR. We also evaluated the viabilities, migration and invasive activities, and tumorigenicities of these SP cells and NSP cells in the presence or absence of salinomycin. Results We demonstrated that i) EMT processes were observed in both RK12V-SP cells and Hec1-SP cells, ii) the level of fibronectin was enhanced in Hec1-SP cells and salinomycin reduced the level of fibronectin expression, iii) salinomycin induced apoptosis and inhibited Wnt signaling, and iv) salinomycin inhibited the proliferation, migration, invasiveness and tumorigenicity of these SP cells. Conclusion This is the first report of an inhibitory effect of salinomycin on the properties of endometrial CSCs.