"Two hits - one stone"; increased efficacy of cisplatin-based therapies by targeting PCNA's role in both DNA repair and cellular signaling.

ABSTRACT: Low response rate and rapid development of resistance against commonly used chemotherapeutic regimes demand new multi-targeting anti-cancer strategies. In this study, we target the stress-related roles of the scaffold protein PCNA with a cell-penetrating peptide containing the PCNA-interacting motif APIM. The APIM-peptide increased the efficacy of cisplatin-based therapies in a muscle-invasive bladder cancer (MIBC) solid tumor model in rat and in bladder cancer (BC) cell lines. By combining multiple omics-levels, from gene expression to proteome/kinome and metabolome, we revealed a unique downregulation of the EGFR/ERBB2 and PI3K/Akt/mTOR pathways in the APIM-peptide-cisplatin combination treated cells. Additionally, the combination treatment reduced the expression of anti-apoptotic protei

SUBMITTER: Sogaard CK 

PROVIDER: S-EPMC6126690 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature