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

Abstract

BackgroundGastric cancer (GC) is the second cause of cancer-related deaths. Methionine enkephalin (MENK), an endogenous opioid peptide, has immunological and antitumor activity.PurposeThe aim of this work was to investigate whether MENK could exhibit activity against human GC in vitro and in vivo.Materials and methodsHuman 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.ResultsThe 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.ConclusionWe conclude that MENK may be a potential drug for the treatment of GC.

CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy

“…Data from previous studies suggest that OGF/OGFR signaling inhibits cell proliferation and survival during development, cancer, wound healing and angiogenesis 12 . Notwithstanding the controversy whether ignition of the OGF/OGFR pathway alone provokes cell apoptosis 13 , 21 , 22 , 36 , 37 , our results strongly suggest that exacerbation of DOX-induced cardiomyocyte apoptosis due to CIRBP ablation is attributed bona fide to OGFR upregulation and activation. Additionally, concomitant alterations in the expression of both p21 and p16, two well-characterized downstream effectors of OGF/OGFR in mediating tonic inhibition of growth and survival 21 , 22 , were observed in our study, further corroborating the contribution of OGFR to cardiomyocyte apoptosis.…”

“…Furthermore, Naltrexone (NTX), a commonly accepted treatment for drug and alcohol addiction as well as a potent antagonist of OGFR 13 , 15 , 24 , successfully rescued the increase in apoptosis induced by CIRBP knockdown. To rule out that this effect was due to the latent action of NTX on opioid receptors 15 , 16 , another agent, Alvimopan (ALV), which has broad-spectrum inhibitory activity capable of pan-targeting multiple opioid receptors, including the δ, κ, and μ receptors 14 , was employed as a control.…”

“…Opioid growth factor receptor (OGFR), an essential part constituting OGF/OGFR signal pathway for cellular survival, was identified as the downstream effector accounting for CIRBP loss-aggravated cardiac apoptosis. OGFR is a non-canonical, perinuclear opioid receptor that does not share structural homology with canonical δ, κ, and μ opioid receptors, and OGF (also known as methionine enkephalin, MENK) is a tonic inhibitory peptide ligand of OGFR 12 , 13 . Our results showed that CIRBP reduced the stability of OGFR mRNA by binding to it.…”

Sanjie Yiliu Formula Inhibits Colorectal Cancer Growth by Suppression of Proliferation and Induction of Apoptosis

“…Many anticancer agents have been reported to arrest the cell cycle at the G 0 /G 1 phase by regulating Bcl-2 and Bax proteins. 45,46 Bcl-2 belongs to a special protein family 47 in which certain members promote apoptosis, including Bax, Bid, and Bad, 48 whereas certain members like Bcl-2 have an inhibition effect on the release of cytochrome c in the cytoplasm from mitochondria, resulting in apoptosis inhibition. 49 Bcl-2 protein is chiefly localized in mitochondria, nuclear membrane, endoplasmic reticulum, and various tumor cells.…”

ZiYinHuaTan Recipe Inhibits Cell Proliferation and Promotes Apoptosis in Gastric Cancer by Suppressing PI3K/AKT Pathway

“…Bcl-2 is the most apoptotic effector of Bcl-2 families, which are important regulators in the PI3K/AKT pathway [32]. Cyclin D1, the downstream regulator of the PI3K/AKT pathway, is an important protein related to the G0/G1 cell cycle checkpoint [33]. e increased expression of Cyclin D1 contributes significantly to tumor development and malignant transformation [34,35].…”