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
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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