Targeting 14-3-3ε-CDC25A interactions to trigger apoptotic cell death in skin cancer
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Thomas R. Holmes1,2, Jenan Al-Matouq1,3, Matti Holmes1, Lauren Nicola1, Justin C. Rudd1, Sándor Lovas1 and Laura A. Hansen1
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
|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
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.
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