Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity In Vitro and In Vivo

• Published in: International journal of molecular sciences Vol. 20; no. 13; p. 3308
• Main Authors: Cao, Can, Zhou, Jie-yun, Xie, Shu-wu, Guo, Xiang-jie, Li, Guo-ting, Gong, Yi-juan, Yang, Wen-jie, Li, Zhao, Zhong, Rui-hua, Shao, Hai-hao, Zhu, Yan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.07.2019; MDPI
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Antidiabetics; Apoptosis; Apoptosis - drug effects; Cancer therapies; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Deoxyribonucleic acid; DNA; Down-Regulation - drug effects; Endocrine therapy; Endometrial cancer; Endometrial Neoplasms - enzymology; Endometrial Neoplasms - pathology; Estrogen Receptor alpha - metabolism; Eukaryotic Initiation Factor-4G - metabolism; Female; Gynecology; Humans; Investigations; Kinases; Medical prognosis; Megestrol - chemistry; Megestrol - pharmacology; Menstruation; Metformin - chemistry; Metformin - pharmacology; Mice, Nude; Norpregnadienes - chemistry; Norpregnadienes - pharmacology; Phosphorylation - drug effects; Proteins; Receptors, Progesterone - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Protein p53 - metabolism; Tumors; Xenograft Model Antitumor Assays; endometrial cancer; nomegestrol acetate; progestins; apoptosis; metformin; mTOR signaling
• DOI: 10.3390/ijms20133308
• ISSN: 1422-0067; 1661-6596

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