Abstract
BackgroundUveal melanoma (UM) is the most common primary intraocular tumor. Hepatic metastasis is the major and direct death-related reason in UM patients. Given that cancer stem-like cells (CSCs) are roots of metastasis, targeting CSCs may be a promising strategy to overcome hepatic metastasis in UM. Salinomycin, which has been identified as a selective inhibitor of CSCs in multiple types of cancer, may be an attractive agent against CSCs thereby restrain hepatic metastasis in UM. The objective of the study is to explore the antitumor activity of salinomycin against UM and clarify its underlying mechanism.MethodsUM cells were treated with salinomycin, and its effects on cell proliferation, apoptosis, migration, invasion, CSCs population, and the related signal transduction pathways were determined. The in vivo antitumor activity of salinomycin was evaluated in the NOD/SCID UM xenograft model and intrasplenic transplantation liver metastasis mouse model.ResultsWe found that salinomycin remarkably obviated growth and survival in UM cell lines and in a UM xenograft mouse model. Meanwhile, salinomycin significantly eliminated CSCs and efficiently hampered hepatic metastasis in UM liver metastasis mouse model. Mechanistically, Twist1 was fundamental for the salinomycin-enabled CSCs elimination and migration/invasion blockage in UM cells.ConclusionsOur findings suggest that targeting UM CSCs by salinomycin is a promising therapeutic strategy to hamper hepatic metastasis in UM. These results provide the first pre-clinical evidence for further testing of salinomycin for its antitumor efficacy in UM patients with hepatic metastasis.
Highlights
Uveal melanoma (UM) is the most common primary intraocular tumor
Data represent mean ± standard deviation (SD). ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001, one-way ANOVA, post hoc comparisons, Tukey’s test. b Dose- and time-dependent of apoptosis-specific cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-3 activation was measured by Western blot after UM cells were incubated with increasing concentrations of salinomycin for 24 h or at 10 μmol/L for the indicated time periods. c UM cells were treated with 10 μmol/L salinomycin for different time, the levels of cytochrome c in the cytosolic extracts were analyzed by Western blot
Salinomycin induces apoptosis in UM cells We evaluated the capability of salinomycin to induce apoptosis
Summary
Uveal melanoma (UM) is the most common primary intraocular tumor. Hepatic metastasis is the major and direct death-related reason in UM patients. Uveal melanoma (UM) is the most common primary intraocular tumor that originates from melanocytes of eye uveal tract [1]. Hepatic metastasis is among the major and direct deathrelated reasons in these UM patients [5]. Agents targeting protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) which are downstream effector molecules of such G protein coupled receptor (GPCR) proteins were evaluated in clinical trials, somehow showing disappointing results [8, 9]. Whether the ongoing clinical trial regard targeting membrane receptor tyrosine kinase c-Met on UM cells can provoke improved survival rate in patients with hepatic metastasis is not clear [8, 10]. The development of innovative and effective drugs for hepatic metastasis in UM still has a high priority
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