整合素与配体精氨酸-甘氨酸-天冬氨酸基序结合的抑制诱导肝星状细胞中 AKT 介导的细胞衰老。
Inhibition of integrin binding to ligand arg-gly-asp motif induces AKT-mediated cellular senescence in hepatic stellate cells.
机构信息
Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, USA.
出版信息
Mol Cell Biochem. 2024 Oct;479(10):2697-2710. doi: 10.1007/s11010-023-04883-0. Epub 2023 Oct 30.
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.
背景与目的
肝星状细胞（HSCs）在肝纤维化发生中起着至关重要的作用。据报道，细胞衰老的诱导可抑制 HSC 的活化。先前，我们证明了小分子精氨酸-甘氨酸-天冬氨酸（RGD）肽模拟物 CWHM12 可抑制 HSC 的活化。本研究探讨了 CWHM12 对 HSCs 的抑制作用是否影响细胞衰老。
方法
使用永生化人 HSC 系 LX-2 和 TWNT-1，通过破坏 RGD 介导的与整联蛋白的结合来评估 CWHM12 对细胞衰老的影响。
结果
CWHM12 诱导 HSCs 细胞周期停滞、衰老相关β-半乳糖苷酶活性、获得衰老相关分泌表型（SASP）和衰老相关蛋白的表达。进一步的实验表明，CWHM12 的作用涉及 AKT 和鼠双微体 2（MDM2）的磷酸化，AKT 磷酸化的抑制逆转了 CWHM12 对 HSCs 的这些作用。
结论
RGD 介导的整联蛋白结合的药理学抑制可诱导活化的 HSCs 衰老。
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