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Mucin 1 作为新型二异喹啉衍生物与抗 MUC1 抗体在 AGS 胃癌细胞中的结合的分子靶点。

Mucin 1 as a Molecular Target of a Novel Diisoquinoline Derivative Combined with Anti-MUC1 Antibody in AGS Gastric Cancer Cells.

机构信息

Department of Biotechnology, Medical University of Bialystok, 15-222 Bialystok, Poland.

Department of Synthesis and Technology of Drugs, Medical University of Bialystok, 15-222 Bialystok, Poland.

出版信息

Molecules. 2021 Oct 28;26(21):6504. doi: 10.3390/molecules26216504.

DOI:10.3390/molecules26216504
PMID:34770912
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8588261/
Abstract

BACKGROUND

The aim of the study was to examine the molecular mechanism of the anticancer action of a monoclonal antibody against MUC1 and a diisoquinoline derivative (OM-86II) in human gastric cancer cells.

METHODS

The cell viability was measured by the MTT assay. The disruption of mitochondrial membrane potential and activity of caspase-8 and caspase-9 was performed by flow cytometry. Fluorescent microscopy was used to confirm the proapoptotic effect of compounds. LC3A, LC3B and Beclin-1 concentrations were analyzed to check the influence of the compounds on induction of autophagy. ELISA assessments were performed to measure the concentration of mTOR, sICAM1, MMP-2, MMP-9 and pro-apoptotic Bax.

RESULTS

The anti-MUC1 antibody with the diisoquinoline derivative (OM-86II) significantly reduced gastric cancer cells' viability. This was accompanied by an increase in caspase-8 and caspase-9 activity as well as high concentrations of pro-apoptotic Bax. We also proved that the anti-MUC1 antibody with OM-86II decreased the concentrations of MMP-9, sICAM1 and mTOR in gastric cancer cells. After 48 h of incubation with such a combination, we observed higher levels of the crucial component of autophagosomes (LC3) and Beclin-1.

CONCLUSIONS

Our study proved that the anti-MUC1 antibody sensitizes human gastric cancer cells to the novel diisoquinoline derivative (OM-86II) via induction of apoptosis and autophagy, and inhibition of selected proteins such as mTOR, sICAM1 and MMP-9.

摘要

背景

本研究旨在探讨针对 MUC1 的单克隆抗体和二异喹啉衍生物（OM-86II）在人胃癌细胞中抗癌作用的分子机制。

方法

通过 MTT 法测定细胞活力。通过流式细胞术测定线粒体膜电位的破坏和半胱天冬酶-8 和半胱天冬酶-9 的活性。荧光显微镜用于确认化合物的促凋亡作用。分析 LC3A、LC3B 和 Beclin-1 浓度以检查化合物对诱导自噬的影响。通过 ELISA 评估测定 mTOR、sICAM1、MMP-2、MMP-9 和促凋亡 Bax 的浓度。

结果

抗 MUC1 抗体与二异喹啉衍生物（OM-86II）显著降低胃癌细胞活力。这伴随着半胱天冬酶-8 和半胱天冬酶-9 活性的增加以及促凋亡 Bax 的高浓度。我们还证明，抗 MUC1 抗体与 OM-86II 降低了胃癌细胞中 MMP-9、sICAM1 和 mTOR 的浓度。在用这种组合孵育 48 小时后，我们观察到自噬体（LC3）和 Beclin-1 的关键成分水平更高。

结论

我们的研究证明，抗 MUC1 抗体通过诱导细胞凋亡和自噬，并抑制 mTOR、sICAM1 和 MMP-9 等选定蛋白，使人类胃癌细胞对新型二异喹啉衍生物（OM-86II）敏感。

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