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Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity In Vitro and In Vivo.
Int J Mol Sci. 2019 Jul 05; 20(13)IJ

Abstract

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.

Authors+Show Affiliations

Pharmacy School, Fudan University, Shanghai 200032, China. Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China. zhuyan@sippr.org.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31284427

Citation

Cao, Can, et al. "Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity in Vitro and in Vivo." International Journal of Molecular Sciences, vol. 20, no. 13, 2019.
Cao C, Zhou JY, Xie SW, et al. Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity In Vitro and In Vivo. Int J Mol Sci. 2019;20(13).
Cao, C., Zhou, J. Y., Xie, S. W., Guo, X. J., Li, G. T., Gong, Y. J., Yang, W. J., Li, Z., Zhong, R. H., Shao, H. H., & Zhu, Y. (2019). Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity In Vitro and In Vivo. International Journal of Molecular Sciences, 20(13). https://doi.org/10.3390/ijms20133308
Cao C, et al. Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity in Vitro and in Vivo. Int J Mol Sci. 2019 Jul 5;20(13) PubMed PMID: 31284427.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity In Vitro and In Vivo. AU - Cao,Can, AU - Zhou,Jie-Yun, AU - Xie,Shu-Wu, AU - Guo,Xiang-Jie, AU - Li,Guo-Ting, AU - Gong,Yi-Juan, AU - Yang,Wen-Jie, AU - Li,Zhao, AU - Zhong,Rui-Hua, AU - Shao,Hai-Hao, AU - Zhu,Yan, Y1 - 2019/07/05/ PY - 2019/06/11/received PY - 2019/06/30/revised PY - 2019/07/03/accepted PY - 2019/7/10/entrez PY - 2019/7/10/pubmed PY - 2019/12/18/medline KW - apoptosis KW - endometrial cancer KW - mTOR signaling KW - metformin KW - nomegestrol acetate KW - progestins JF - International journal of molecular sciences JO - Int J Mol Sci VL - 20 IS - 13 N2 - 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/31284427/Metformin_Enhances_Nomegestrol_Acetate_Suppressing_Growth_of_Endometrial_Cancer_Cells_and_May_Correlate_to_Downregulating_mTOR_Activity_In_Vitro_and_In_Vivo_ L2 - http://www.mdpi.com/resolver?pii=ijms20133308 DB - PRIME DP - Unbound Medicine ER -