Inhibition of integrin binding to ligand arg-gly-asp motif induces AKT-mediated cellular senescence in hepatic stellate cells.

IF 3.5 2区生物学 Q3 CELL BIOLOGY

Molecular and Cellular Biochemistry Pub Date : 2024-10-01 Epub Date: 2023-10-30 DOI:10.1007/s11010-023-04883-0

Kensuke Kitsugi, Hidenao Noritake, Moe Matsumoto, Tomohiko Hanaoka, Masahiro Umemura, Maho Yamashita, Shingo Takatori, Jun Ito, Kazuyoshi Ohta, Takeshi Chida, Barbara Ulmasov, Brent A Neuschwander-Tetri, Takafumi Suda, Kazuhito Kawata

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引用次数: 0

Abstract

Background & aims: Hepatic stellate cells (HSCs) play an essential role in liver fibrogenesis. The induction of cellular senescence has been reported to inhibit HSC activation. Previously, we demonstrated that CWHM12, a small molecule arginine-glycine-aspartic acid (RGD) peptidomimetic compound, inhibits HSC activation. This study investigated whether the inhibitory effects of CWHM12 on HSCs affected cellular senescence.

Methods: The immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on cellular senescence via the disruption of RGD-mediated binding to integrins.

Results: CWHM12 induces cell cycle arrest, senescence-associated beta-galactosidase activity, acquisition of senescence-associated secretory phenotype (SASP), and expression of senescence-associated proteins in HSCs. Further experiments revealed that the phosphorylation of AKT and murine double minute 2 (MDM2) was involved in the effects of CWHM12, and the inhibition of AKT phosphorylation reversed these effects of CWHM12 on HSCs.

Conclusions: Pharmacological inhibition of RGD-mediated integrin binding induces senescence in activated HSCs.

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整合素与配体arg-gly-asp基序结合的抑制诱导肝星状细胞中AKT介导的细胞衰老。

背景与目的：肝星状细胞（HSCs）在肝纤维化发生中起着重要作用。据报道，诱导细胞衰老可抑制HSC的活化。此前，我们证明了CWHM12，一种小分子精氨酸-甘氨酸-天冬氨酸（RGD）肽模拟化合物，可以抑制HSC的激活。本研究探讨了CWHM12对HSC的抑制作用是否影响细胞衰老。方法：使用永生化的人HSC系LX-2和TWNT-1，通过破坏RGD介导的与整合素的结合来评估CWHM12对细胞衰老的影响。结果：CWHM12诱导HSC细胞周期停滞、衰老相关β-半乳糖苷酶活性、衰老相关分泌表型（SASP）的获得和衰老相关蛋白的表达。进一步的实验表明，AKT和小鼠双分钟2（MDM2）的磷酸化参与了CWHM12的作用，并且对AKT磷酸化的抑制逆转了CWHM12中对HSC的这些作用。结论：RGD介导的整合素结合的药理学抑制诱导活化HSC衰老。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular and Cellular Biochemistry 生物-细胞生物学

CiteScore

8.30

自引率

2.30%

发文量

293

审稿时长

1.7 months

期刊介绍： Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.