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The novel mechanism of anticancer effect on gastric cancer through inducing G0/G1 cell cycle arrest and caspase-dependent apoptosis in vitro and in vivo by methionine enkephalin

Authors Wang X, Tian J, Jiao X, Geng J, Wang R, Liu N, Gao X, Griffin N, Gao Y, Shan F

Received 26 June 2018

Accepted for publication 4 August 2018

Published 18 October 2018 Volume 2018:10 Pages 4773—4787

DOI https://doi.org/10.2147/CMAR.S178343

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Antonella D'Anneo


Xiaonan Wang,1 Jing Tian,1 Xue Jiao,2 Jin Geng,3 Reizhe Wang,4 Ning Liu,5 Xinghua Gao,6 Noreen Griffin,7 Yuan Gao,8 Fengping Shan1

1Department of Immunology, College of Basic Medical Science, China Medical University, Shenyang, China; 2Department of Translational Medicine, No. 4 Teaching Hospital, China Medical University, Shenyang, China; 3Department of Ophthalmology, China Medical University, Shenyang, China; 4Department of Gynecology, No. 1 Teaching Hospital, China Medical University, Shenyang, China; 5Department of Gynecologic Oncology, Shengjing Hospital, 6Department of Dermatology, No. 1 Teaching Hospital, China Medical University, Shenyang, China; 7Immune Therapeutics, Inc., Orlando, FL, USA; 8Faculty of Information and Engineering, Northeastern University, Shenyang, China

Background: Gastric cancer (GC) is the second cause of cancer-related deaths. Methionine enkephalin (MENK), an endogenous opioid peptide, has immunological and antitumor activity.
Purpose: The aim of this work was to investigate whether MENK could exhibit activity against human GC in vitro and in vivo.
Materials and methods: Human GC cells were treated with MENK. Cell viability, colony formation, cell morphology, cell cycle, and apoptosis were assessed. The effects of MENK on gene expression of OGFr, Bax, BCL-2, caspase-3, PARP, Ki67, cyclin D1, c-myc, survivin were quantifed by qRT-PCR. Western blot was used to analyze the effects of MENK on protein expression of OGFr, Bax, BCL-2, caspase-3, PARP. The anti-tumor activity of MENK in gastic carcinoma was also investigated with animal experiments.
Results: The results indicate that MENK could significantly inhibit the growth of human GC cells SGC7901 and HGC27 in a concentration- and time-dependent manner, decrease the number of cell colonies, and arrest cell cycle in the G0/G1 phase by causing a decrease in Ki67, cyclin D1, and c-myc mRNA. Furthermore, MENK could induce tumor cell apoptosis associated with the upregulation of Bax, a corresponding downregulation of BCL-2 and survivin, and activation of caspase-3 and PARP. Moreover, MENK upregulated the expression of opioid receptors (OGFr) in SGC7901 and HGC27 cells. The interaction between MENK and OGFr in SGC7901 and HGC27 cells appears to be essential for the antitumor activity of MENK.
Conclusion: We conclude that MENK may be a potential drug for the treatment of GC.

Keywords: MENK, GC cells, OGFr, cell cycle, apoptosis

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