Cleaved Caspase-3 transcriptionally regulates angiogenesis promoting chemotherapy resistance.
Fiche publication
Date publication
octobre 2019
Journal
Cancer research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ARNOULD Laurent, Dr BOIDOT Romain, Pr GHIRINGHELLI François, Dr COLLIN Bertrand, Dr VEGRAN Frédérique, Dr DERANGERE Valentin
Tous les auteurs :
Bernard A, Chevrier S, Beltjens F, Dosset M, Viltard E, Lagrange A, Dérangère V, Oudot A, Ghiringhelli F, Collin B, Apetoh L, Feron O, Chen S, Arnould L, Végran F, Boidot R
Lien Pubmed
Résumé
Caspases are well-known for their role in apoptosis. Recently, non-apoptotic roles of caspases have been identified, however, these non-canonical roles are not well-documented and the mechanisms involved are not fully understood. Here, we studied the role of cleaved caspase-3 using human- and mouse-proficient caspase-3 cancer cell lines and human-deficient caspase-3 cancer cells. Cleaved caspase-3 functioned as a transcription factor and directly bound to DNA. A DNA binding domain was identified in the small subunit of caspase-3 and an active conformation was essential for caspase-3 transcriptional activity. Caspase-3 DNA binding enhanced angiogenesis by upregulating the expression of pro-angiogenic genes and by activating pathways that promoted endothelial cell activation. Some pro-apoptotic genes were downregulated in caspase-3 proficient cells. Inhibiting caspase-3 increased the efficacy of chemotherapy and decreased spontaneous tumor development. These data highlight a novel non-apoptotic role of caspase-3 and suggest that cleaved caspase-3 could be a new therapeutic target in cancer.
Référence
Cancer Res.. 2019 Oct 14;: