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

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

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

Affiliation

Kitsugi K; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Noritake H; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan. noritake@hama-med.ac.jp.
Matsumoto M; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Hanaoka T; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Umemura M; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Yamashita M; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Takatori S; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Ito J; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Ohta K; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Chida T; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Ulmasov B; Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, USA.
Neuschwander-Tetri BA; Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, USA.
Suda T; Division of Respiratory Medicine, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Kawata K; Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

Mol Cell Biochem ; 2023 Oct 30.

Article in En | MEDLINE | ID: mdl-37902885

ABSTRACT

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.