1. Targeting 14-3-3ε activates apoptotic signaling to prevent cutaneous squamous cell carcinoma
- Author
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Lauren Nicola, Matti Holmes, Jenan Al Matouq, Justin G. Madson, Laura A. Hansen, Nicholas Palermo, Celia R. Bloom, Justin C. Rudd, Natasha A Sioda, Thomas R. Holmes, and Sándor Lovas
- Subjects
Keratinocytes ,Male ,0301 basic medicine ,Cytoplasm ,Cancer Research ,Programmed cell death ,Skin Neoplasms ,Carcinogenesis ,9,10-Dimethyl-1,2-benzanthracene ,Antineoplastic Agents ,Apoptosis ,Human skin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Survivin ,medicine ,Animals ,Humans ,cdc25 Phosphatases ,Protein kinase B ,Mice, Knockout ,integumentary system ,business.industry ,Cancer ,Neoplasms, Experimental ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,14-3-3 Proteins ,030220 oncology & carcinogenesis ,Carcinogens ,Carcinoma, Squamous Cell ,Cancer research ,Tetradecanoylphorbol Acetate ,Female ,Protein Multimerization ,Signal transduction ,Skin cancer ,business - Abstract
More than a million cases of cutaneous squamous cell carcinoma are diagnosed in the USA each year, and its incidence is increasing. Most of these malignancies arise from premalignant lesions, providing an opportunity for intervention before malignant progression. We previously documented how cytoplasmic mislocalization of CDC25A in premalignant and malignant skin cancers confers resistance to apoptotic cell death via a mechanism that depends on its interaction with 14-3-3ε. From these data, we hypothesized that 14-3-3ε overexpression drives skin tumor development and progression, such that targeting 14-3-3ε may be a useful strategy for skin cancer treatment. Like CDC25A, 14-3-3ε was overexpressed and mislocalized to the cytoplasm of both benign and malignant human skin cancer. Skin-targeted deletion of the 14-3-3ε gene reduced skin tumor development by 75% and blocked malignant progression. 14-3-3ε suppressed apoptosis through activation of Akt, leading to inhibition of BCL2 associated agonist of cell death and upregulation of Survivin. Using virtual tetrapeptide libraries, we developed a novel peptide that specifically blocked 14-3-3ε heterodimerization and thereby prevented its interaction with CDC25A. The peptide reduced prosurvival signaling, killed skin cancer cells and reduced skin tumor growth in xenograft. Normal skin keratinocytes were unaffected by inhibition or deletion of 14-3-3ε. Thus, targeting of 14-3-3ε dimerization is a promising strategy for the treatment of premalignant skin lesions.
- Published
- 2020