This study investigated the effect of a novel progestin and its combination with metformin\non the growth of endometrial cancer (EC) cells. Inhibitory effects of four progestins, including\nnomegestrol acetate (NOMAC), medroxyprogesterone acetate, levonorgestrel, and cyproterone\nacetate, were evaluated in RL95-2, HEC-1A, and KLE cells using cell counting kit-8 assay. Flow\ncytometry was performed to detect cell cycle and apoptosis. The activity of Akt (protein kinase B),\nmTOR (mammalian target of rapamycin) and its downstream substrates 4EBP1 (4E-binding protein 1)\nand eIF4G (Eukaryotic translation initiation factor 4G) were assayed by Western blotting. Nude\nmice were used to assess antitumor effects in vivo. NOMAC inhibited the growth of RL95-2 and\nHEC-1A cells, accompanied by arresting the cell cycle at G0/G1 phase, inducing apoptosis, and\nmarkedly down-regulating the level of phosphorylated mTOR/4EBP1/eIF4G in both cell lines (p < 0.05).\nMetformin significantly increased the inhibitory effect of and apoptosis induced by NOMAC and\nstrengthened the depressive effect of NOMAC on activity of mTOR and its downstream substrates,\ncompared to their treatment alone (p < 0.05). In xenograft tumor tissues, metformin (100 mg/kg)\nenhanced the suppressive effect of NOMAC (100 mg/kg) on mTOR signaling and increased the\naverage concentration of NOMAC by nearly 1.6 times compared to NOMAC treatment alone. Taken\ntogether, NOMAC suppressing the growth of EC cells likely correlates to down-regulating the activity\nof the mTOR pathway and metformin could strengthen this effect. Our findings open a new window\nfor the selection of progestins in hormone therapy of EC.
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