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

Abstract

// Thomas R. Holmes 1 , 2 , Jenan Al-Matouq 1 , 3 , Matti Holmes 1 , Lauren Nicola 1 , Justin C. Rudd 1 , Sándor Lovas 1 and Laura A. Hansen 1 1 Creighton University School of Medicine, Department of Biomedical Sciences, Omaha, NE, USA 2 Current Address: Northwestern University, Chicago, IL, USA 3 Current Address: Mohammed Al-mana College for Medical Science, Dammam, Kingdom of Saudi Arabia Correspondence to: Sándor Lovas, email: [email protected] Laura A. Hansen, email: [email protected] Keywords: skin cancer; squamous cell carcinoma; CDC25A; 14-3-3ε; apoptosis Received: July 17, 2019     Accepted: July 21, 2020     Published: September 01, 2020 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-14-3-3ε interactions may be an effective strategy for inducing skin cancer cell apoptosis. Co-immunoprecipitation revealed that CDC25A associated with 14-3-3ε, 14-3-3γ and 14-3-3ζ in SCC cells but not normal keratinocytes. 14-3-3ε and CDC25A activated Akt/BAD/Survivin pro-survival signaling. To target the interaction of 14-3-3ε 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 14-3-3ε binding to CDC25A. Peptides pT (IC 50 = 22.1 μM), and pS (IC 50 = 29 μM) induced SCC cell death and blocked 14-3-3ε 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 14-3-3ε-CDC25A interactions for skin cancer treatment.

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