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 (IC50 = 22.1 μM), and pS (IC50 = 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.
Highlights
Skin cancer is the most common malignancy in humans, with squamous cell carcinoma (SCC) representing 20% of cases [1]
In order to develop a strategy for targeting cell division cycle 25A (CDC25A) binding to 14-3-3ε, we first needed to determine which 14-3-3 isoforms are expressed in skin cancer and associate with CDC25A in skin cancer cells
We showed that CDC25A associated with 14-3-3ε, 14-3-3γ and 14-3-3ζ in SCC cells
Summary
Skin cancer is the most common malignancy in humans, with squamous cell carcinoma (SCC) representing 20% of cases [1]. The anti-apoptotic activity of CDC25A was reliant upon its ability to associate with the 14-3-3 family of signaling proteins through its 14-3-3 binding region around residues phosphoserine-178 and phosphothreonine-507 [6]. 143-3 proteins associate with many functionally diverse molecules through conserved either phosphoserine or phosphothreonine peptide motifs on target proteins, affecting apoptosis, proliferation, metabolism and migration [7,8,9]. Association of CDC25A with 14-3-3 proteins occurs in response to cell cycle checkpoint activation following ultraviolet (UV) radiation-induced DNA damage [6, 10, 11]
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