Targeting 14-3-3?-CDC25A interactions to trigger apoptotic cell death in skin cancer.

ABSTRACT: Non-melanoma skin cancer is the most common form of cancer worldwide. We previously documented an anti-apoptotic role for CDC25A in cutaneous squamous cell carcinoma (SCC), an activity dependent on its association with 14-3-3 proteins. We hypothesized that targeting CDC25A-14-3-3? interactions may be an effective strategy for inducing skin cancer cell apoptosis. Co-immunoprecipitation revealed that CDC25A associated with 14-3-3?, 14-3-3? and 14-3-3? in SCC cells but not normal keratinocytes. 14-3-3? and CDC25A activated Akt/BAD/Survivin pro-survival signaling. To target the interaction of 14-3-3? with CDC25A for cancer therapy, we developed two novel phospho-peptides, pS and pT, corresponding to each of the 14-3-3 binding sites of CDC25A, to specifically interfere with 14-3-3? binding to CDC25A. Peptides pT (IC50 = 22.1 ?M), and pS (IC50 = 29 ?M) induced SCC cell death and blocked 14-3-3? binding to CDC25A. pS or pT treatment of SCC xenografts increased apoptotic cell death and decreased pro-survival P-Akt (S473) and Survivin, demonstrating the effectiveness of the peptides in vivo. These findings lay a framework for the further development of peptides to target 14-3-3?-CDC25A interactions for skin cancer treatment.

SUBMITTER: Holmes TR 

PROVIDER: S-EPMC7476737 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature