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Novel Strategy for Treating Premalignant Skin Lesions Under Study

By: Nahae Kim, MPH
Posted: Wednesday, October 28, 2020

For the prevention and treatment of skin cancer, targeting 14-3-3ε proteins may be an effective strategy. According to research findings published in Carcinogenesis, the oncogenic mechanism of 14-3-3ε appears to be linked to CDC25A-mediated inhibition of apoptosis, and its expression is upregulated in squamous cell carcinoma. Laura A. Hansen, PhD, of Creighton University School of Medicine, Omaha, and colleagues observed that skin deficient in these proteins was resistant to cutaneous carcinogenesis and subsequently developed an inhibitor to selectively target these proteins in squamous cell carcinoma cells.

“Our de novo designed peptide, ES1P2 is more effective at killing squamous cell carcinoma cells than fluorouracil, the most effective approved therapy for premalignant skin cancers. Furthermore, our peptide avoided toxicity to normal skin or skin cells in culture, suggesting minimal side effects with topical use clinically,” the investigators concluded.

To further elucidate the role of 14-3-3ε, the 14-3-3ε gene was silenced in cutaneous squamous cell carcinoma cell lines of humanized mice. In response, skin tumor development decreased by 75%, and malignant progression ceased. Furthermore, the deletion of 14-3-3ε did not seem to trigger a stress response in normal epidermis. The study authors supported 14-3-3ε’s dimerization as a key activator of Akt and binding partner of CDC25A as part of an antiapoptotic cascade.

The tetrapeptide ES1P2 was then designed to target the N-terminal heterodimerization region of 14-3-3ε. Mice injected with squamous cell carcinoma cell lines were either treated with ES1P2 or an intratumoral injection daily for 2 days or every other day for 2 weeks. ES1P2 decreased P-Akt and Survivin levels, reducing the growth of squamous cell carcinoma in the xenograft by 50%, whereas normal cells remained unaffected.

Disclosure: The study authors reported no conflicts of interest.



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