1. Targeting 14-3-3ε-CDC25A interactions to trigger apoptotic cell death in skin cancer
- Author
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Justin C. Rudd, Thomas R. Holmes, Sándor Lovas, Jenan Al-Matouq, Laura A. Hansen, Lauren Nicola, and Matti Holmes
- Subjects
squamous cell carcinoma ,CDC25A ,Programmed cell death ,skin cancer ,Chemistry ,apoptosis ,Cancer ,medicine.disease ,14-3-3ε ,Oncology ,In vivo ,Apoptosis ,Survivin ,medicine ,Cancer research ,Skin cancer ,Protein kinase B ,Research Paper - 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-14-3-3e interactions may be an effective strategy for inducing skin cancer cell apoptosis. Co-immunoprecipitation revealed that CDC25A associated with 14-3-3e, 14-3-3γ and 14-3-3ζ in SCC cells but not normal keratinocytes. 14-3-3e and CDC25A activated Akt/BAD/Survivin pro-survival signaling. To target the interaction of 14-3-3e 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 14-3-3e binding to CDC25A. Peptides pT (IC50 = 22.1 μM), and pS (IC50 = 29 μM) induced SCC cell death and blocked 14-3-3e 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 14-3-3e-CDC25A interactions for skin cancer treatment.
- Published
- 2020