Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity In Vitro and In Vivo
Autor: | Shuwu Xie, Can Cao, Yang Wenjie, Yi-juan Gong, Hai-hao Shao, Yan Zhu, Ruihua Zhong, Xiangjie Guo, Guoting Li, Zhao Li, Jieyun Zhou |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Nomegestrol acetate Norpregnadienes Apoptosis Cell Cycle Proteins Pharmacology lcsh:Chemistry chemistry.chemical_compound 0302 clinical medicine Phosphorylation lcsh:QH301-705.5 Spectroscopy TOR Serine-Threonine Kinases Cyproterone acetate General Medicine Cell cycle Metformin Computer Science Applications 030220 oncology & carcinogenesis endometrial cancer Female Receptors Progesterone medicine.drug medicine.drug_class Down-Regulation Mice Nude Catalysis Article Inorganic Chemistry 03 medical and health sciences Cell Line Tumor medicine Animals Humans Physical and Theoretical Chemistry Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Cell Proliferation Organic Chemistry Estrogen Receptor alpha Cell Cycle Checkpoints Megestrol Xenograft Model Antitumor Assays Endometrial Neoplasms nomegestrol acetate 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 chemistry progestins mTOR signaling Tumor Suppressor Protein p53 Eukaryotic Initiation Factor-4G Progestin |
Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 20, Iss 13, p 3308 (2019) Volume 20 Issue 13 |
ISSN: | 1422-0067 |
Popis: | 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. |
Databáze: | OpenAIRE |
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