Sorafenib-mediated cleavage of p62 initiates cellular senescence as a mechanism to evade its anti-hepatocellular carcinoma efficacy.
Oncogene
; 43(40): 3003-3017, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-39232218
ABSTRACT
Hepatocellular carcinoma (HCC) stands as one of the most aggressively advancing and lethal malignancies. Sorafenib is presently endorsed as a primary therapy for advanced liver cancer, but its resistance presents a formidable challenge. Previous studies have implicated a connection between post-sorafenib discontinuation rebound and the development of drug resistance, yet the underlying mechanism remains elusive. In this study, we discerned that Sorafenib induced a senescent phenotype in HCC cells and caused a cleavage of ubiquitin-binding protein p62. Mechanistic studies establish that truncated p62 drives cellular senescence by promoting proteasome-dependent degradation of 4EBP1. Furthermore, truncated p62 induced specific ubiquitination of 4EBP1. Crucially, virtual drug screening uncovered that dacinostat inhibited cellular senescence by blocking sorafenib-induced p62 cleavage. In summary, our findings imply that truncated p62 from sorafenib cleavage promotes senescence via 4EBP1 degradation. The prevention of p62 cleavage could emerge as a crucial strategy for impeding the sorafenib-induced cellular senescence.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Senescencia Celular
/
Carcinoma Hepatocelular
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Sorafenib
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Neoplasias Hepáticas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Oncogene
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Reino Unido