Abstract
There is an urgent need to identify targeting molecules to control invasion and metastasis in cancer patients. We first isolated cancer stem cells (CSCs) from SKOV3 ovarian cancer cells and then investigated the role of melatonin in invasiveness and migration of CSCs compared to SKOV3 cells. The proportion of CSCs in SKOV3 cells was as low as 1.28% with overexpression of both CD133 and CD44. The ability of spheroid formation along with SOX2 overexpression revealed a high self-renewal potential in isolated cells. Melatonin (3.4 mM) inhibited proliferation of CSCs by 23% which was confirmed by a marked decrease in protein expression of Ki67, as a proliferation marker. Applying luzindole, a melatonin receptor 1, 2 inhibitor, partially abolished anti-proliferative effect of melatonin. Melatonin also decreased Epithelial mesenchymal transition (EMT) related gene expressions including ZEB1, ZEB2, snail and vimentin with increase in E-cadherin as a negative EMT regulator. Incubation of CSCs with melatonin showed a marked decrease in matrix metalloproteinase 9 (MMP9) expression and activity. Melatonin also inhibited CSCs migration in a partially receptor dependent and PI3k and MAPK independent manner. Melatonin can be considered as an important adjuvant to control invasion and metastasis especially in patients with high melatonin receptor expression.
Highlights
Ovarian cancer is the fifth most common gynecological malignancy
Only 1.2 ± 0.25% of the cells were double positive for both CD133 and CD44 markers in SKOV3 cell line (Fig. 1a)
Immunofluorescence staining on isolated cells demonstrated that the majority of the cells were double positive for CD133 and CD44 markers compared to SKOV3 cells (Fig. 1b)
Summary
Ovarian cancer is the fifth most common gynecological malignancy. Most of the patients are diagnosed in advanced stages. Increasing evidence represented the existence of highly tumorigenic cells with stem cell properties within the various tumor microenvironments including ovarian cancer[2]. CSCs are critically contributed to tumor initiation, metastasis, relapse and resistance to chemotherapy[2] Targeting these cells can be considered as a novel strategy for efficient cancer therapy. Very few studies have investigated the effects of melatonin and underlying mechanisms on CSCs. It has been reported that melatonin inhibits self-renewal and related signaling pathways of glioma cancer stem cells[6]. We first isolated CSCs from SKOV3 ovarian cancer cell line, and determined the stemness and self-renewal ability of these cells through both flow cytometry analysis for cell specific markers including CD133, CD44 and SOX2, as well as spheroid formation assay. Our results suggest that melatonin can be considered as an important modulator to suppress tumor progression via targeting CSCs proliferation, migration and invasion especially in the patients with high melatonin receptor expression
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