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Apelin is a bioactive adipocytokine that is highly expressed by various tissues in the human body with serum concentration 1,31 ± 0,12 ng/ml. Several studies show that alterations in the secretion of adipokines affect cell proliferation, apoptosis, tumor invasion and angiogenesis. We previously demonstrated that apelin and its receptor (APLNR) are expressed by ovarian tumor cell lines and acts as a mitogenic factor in these cells. It is well known that 17β-estradiol (E2) and insulin-like growth factor 1 (IGF-1) plays a key role in ovarian cancer progression. Moreover, apelin by binding to its receptor, share the same signaling pathways with E2 and IGF-1 such as ERK1/2. Thus, we investigated whether apelin can interact with E2 or IGF-1 and regulate ovarian cancer progression. The human ovarian serous carcinoma cell line OVCAR-3 were obtained from the ATCC, and cultured in RPMI 1640 medium supplemented with 15% FBS. Cell proliferation was measured using the CellTiter-Glo Luminescent Cell Viability Assay reagent. Total RNA isolation and cDNA synthesis were carried out using the TaqMan Gene Expression Cells-to-CT. Statistical analysis was performed using one-way ANOVA followed by Tukey's test. The level of significance was set at P < 0.05. Consistent with previous results, we found that apelin (2 ng/ml), E2 (1nM) and IGF-1 (100 ng/ml) stimulated OVCAR-3 cell proliferation (160%, 127% and 135% relative to that of the control, respectively; p < 0.05). The combined treatment of apelin and IGF-1 does not change the proliferative effect of these compounds. However, treatment of E2 and apelin together decreased cell proliferation to the control cell level (111%; p < 0.05). Thus, we examined whether apelin (2 ng/ml) could affect the mRNA expression of ESR1, ESR2, and GPER1 in OVCAR-3 cells. We observed no difference in selected receptors expression between apelin-treated and control cells. Considering an antagonistic effect of apelin and E2 together on cell proliferation, we then determined whether the non-genomic ERK1/2 signaling pathway was involved in these effect. Pretreatment of OVCAR-3 cells with the ERK1/2 inhibitor PD098059 (5 µmol/L) reversed the stimulatory effects of apelin and E2 alone on cell proliferation (102% and 101%, respectively; p < 0.05). Exposure of the cells to the combination of apelin and E2 with PD098059 also decreased to the control level OVCAR-3 cell proliferation (111%; p < 0.05) indicating that non-genomic ERK1/2 pathway is not involved in this process. Taken together, our results suggest that ERK1/2 signaling pathway is involved in apelin and E2 regulated ovarian cancer cell proliferation. We also showed that antagonistic effect of apelin and E2 together is not mediated by ERK1/2 pathway and further studies are needed. This work was supported by the National Science Centre, Poland (NCN, grant number 2016/21/N/NZ5/00161).
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