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Acetate decreases PVR/CD155 expression via PI3K/AKT pathway in cancer cells.

ABSTRACT: In recent years, restoring anti-tumor immunity has garnered a growing interest in cancer treatment. As potential therapeutics, immune checkpoint inhibitors have demonstrated benefits in many clinical studies. Although various methods have been applied to suppress immune checkpoints to boost anti-tumor immunity, including the use of immune checkpoint inhibitors, there are still unmet clinical needs to improve the response rate of cancer treatment. Here, we show that acetate can suppress the expression of poliovirus receptor (PVR/CD155), a ligand for immune checkpoint, in colon cancer cells. We demonstrated that acetate treatment could enhance effector responses of CD8+ T cells by decreasing the expression of PVR/CD155 in cancer cells. We also found that acetate could reduce the expression of PVR/CD155 by deactivating the PI3K/AKT pathway. These results demonstrate that acetate-mediated expression of PVR/ CD155 in cancer cells might potentiate the anti-tumor immunity in the microenvironment of cancer. Our findings indicate that maintaining particular acetate concentrations could be a complementary strategy in current cancer treatment. [BMB Reports 2021; 54(8): 431-436].

SUBMITTER: Tran NL

PROVIDER: S-EPMC8411046 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Acetate decreases PVR/CD155 expression via PI3K/AKT pathway in cancer cells.

Tran Na Ly NL Lee In Kyu IK Choi Jungkyun J Kim Sang-Heon SH Oh Seung Ja SJ

BMB reports 20210801 8

In recent years, restoring anti-tumor immunity has garnered a growing interest in cancer treatment. As potential therapeutics, immune checkpoint inhibitors have demonstrated benefits in many clinical studies. Although various methods have been applied to suppress immune checkpoints to boost anti-tumor immunity, including the use of immune checkpoint inhibitors, there are still unmet clinical needs to improve the response rate of cancer treatment. Here, we show that acetate can suppress the expre ...[more]

PMID: 34353426

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Project description:Gastric cancer (GC) is among the five most common malignancies worldwide. Traditional chemotherapy cannot efficiently treat the disease and faces the problems of side effects and chemoresistance. Polygoni orientalis Fructus (POF), with flavonoids as the main bioactive compounds, exerts anti-cancer potential. In this study, we compared the anti-GC effects of the main flavonoids from POF and investigated the anti-cancer effects of eriodictyol towards GC both in vitro and in vivo. CCK-8 assays were performed to examine the inhibitory effects of common flavonoids from POF on GC cell viability. Colony formation assays were used to determine cell proliferation after eriodictyol treatment. Cell cycle distribution was analyzed using flow cytometry. Induction of apoptosis was assessed with Annexin V/PI staining and measurement of related proteins. Anti-cancer effects in vivo were investigated using a xenograft mouse model. Potential targets of eriodictyol were clarified by network pharmacological analysis, evaluated by molecular docking, and validated with Western blotting. We found that eriodictyol exhibited the most effective inhibitory effect on cell viability of GC cells among the common flavonoids from POF including quercetin, taxifolin, and kaempferol. Eriodictyol suppressed colony formation of GC cells and induced cell apoptosis. The inhibitory effects of eriodictyol on tumor growth were also validated using a xenograft mouse model. Moreover, no obvious toxicity was identified with eriodictyol treatment. Network pharmacology analysis revealed that PI3K/AKT signaling ranked first among the anti-GC targets. The molecular docking model of eriodictyol and PI3K was constructed, and the binding energy was evaluated. Furthermore, efficient inhibition of phosphorylation and activation of PI3K/AKT by eriodictyol was validated in GC cells. Taken together, our results identify eriodictyol as the most effective anti-GC flavonoids from POF and the potential targets of eriodictyol in GC. These findings suggest that eriodictyol has the potential to be a natural source of anti-GC agents.

Project description:BackgroundEsophageal cancer is still a leading cause of death among all tumors in males, with unsatisfactory responses to novel immunotherapies such as anti-PD-1 agents. Herein, we explored the role of CD155 in esophageal squamous cell cancer (ESCA) and its underlying molecular mechanisms.MethodsPublicly available datasets were used for differential gene expression and immune infiltration analyses, and their correlation with patient survival. A total of 322 ESCA and 161 paracancer samples were collected and evaluated by performing immunohistochemistry and the H score was obtained by performing semiquantitative analysis. In vitro transfection of ESCA cell lines with lentivirus vectors targeting CD155 was performed to knockdown the protein. These cells were analyzed by conducting RNA sequencing, and the effects of CD155 knockdown on cell cycle and apoptosis were verified with flow cytometry and Western blotting. In addition, in vivo experiments using these engineered cell lines were performed to determine the role of CD155 in tumor formation. A small interfering RNA-mediated knockdown of Nectin3 was used to determine whether it phenocopied the profile of CD155 knockdown.ResultsCD155 is highly expressed in ESCA tissues and is positively associated with PD1, PDL1, CD4, IL2RA, and S100A9 expression. Furthermore, CD155 knockdown inhibited ESCA cells' proliferation by impairing the cell cycle and inducing cell apoptosis. Bioinformatics analysis of the gene expression profile of these engineered cells showed that CD155 mainly contributed to the regulation of PI3K/Akt and MAPK signals. The downregulation of Nectin3 expression phenocopied the profile of CD155 knockdown.DiscussionCD155 may cooperate with PD-1/PD-L1 to support ESCA proliferation in ways other than regulating its underlying immune mechanisms. Indeed, CD155 downregulation can impair ESCA cell pro-cancerous behavior via the inhibition of the PI3K/Akt and MAPK signaling pathways. Moreover, Nectin3 may be a ligand of CD155 and participate in the regulation of ESCA cells' proliferation. Hence, the inhibition of CD155 may enhance the therapeutic effect of anti-PD-1 immunotherapies in ESCA.

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Acetate decreases PVR/CD155 expression via PI3K/AKT pathway in cancer cells.

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Acetate decreases PVR/CD155 expression via PI3K/AKT pathway in cancer cells.

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