Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells

Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells

Late‐stage colorectal cancer (CRC) is still a clinically challenging problem. The activity of the tumor suppressor p53 is regulated via post‐translational modifications (PTMs). While the relevance of p53 C‐terminal acetylation for transcriptional regulation is well defined, it is unknown whether thi...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Christian Marx, Jürgen Sonnemann, Mandy Beyer, Oliver D. K. Maddocks, Sergio Lilla, Irene Hauzenberger, Andrea Piée‐Staffa, Kanstantsin Siniuk, Suneetha Nunna, Lisa Marx‐Blümel, Martin Westermann, Tobias Wagner, Felix B. Meyer, René Thierbach, Christina S. Mullins, Said Kdimati, Michael Linnebacher, Francesco Neri, Thorsten Heinzel, Zhao‐Qi Wang, Oliver H. Krämer
Formato: article
Lenguaje:EN
Publicado: Wiley 2021
Materias:
acetylation
apoptosis
BAK
mitochondria
p53
replication stress
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Acceso en línea:https://doaj.org/article/0b74c48fb69942fab1d217753fe500f2
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
Descripción
Sumario:Late‐stage colorectal cancer (CRC) is still a clinically challenging problem. The activity of the tumor suppressor p53 is regulated via post‐translational modifications (PTMs). While the relevance of p53 C‐terminal acetylation for transcriptional regulation is well defined, it is unknown whether this PTM controls mitochondrially mediated apoptosis directly. We used wild‐type p53 or p53‐negative human CRC cells, cells with acetylation‐defective p53, transformation assays, CRC organoids, and xenograft mouse models to assess how p53 acetylation determines cellular stress responses. The topoisomerase‐1 inhibitor irinotecan induces acetylation of several lysine residues within p53. Inhibition of histone deacetylases (HDACs) with the class I HDAC inhibitor entinostat synergistically triggers mitochondrial damage and apoptosis in irinotecan‐treated p53‐positive CRC cells. This specifically relies on the C‐terminal acetylation of p53 by CREB‐binding protein/p300 and the presence of C‐terminally acetylated p53 in complex with the proapoptotic BCL2 antagonist/killer protein. This control of C‐terminal acetylation by HDACs can mechanistically explain why combinations of irinotecan and entinostat represent clinically tractable agents for the therapy of p53‐proficient CRC.

Ejemplares similares