Mutant p53 reactivator SLMP53-2 hinders ultraviolet B radiation-induced skin carcinogenesis

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Mutant p53 reactivator SLMP53-2 hinders ultraviolet B radiation-induced skin carcinogenesis

Thursday, 13.01.2022

Skin cancer (SC) is one of the most common types of cancer in the world population, with an increasing annual incidence rate. The p53 protein plays a crucial role in skin tumorigenesis, and its function is often compromised due to mutations induced by ultraviolet radiation (UVB). Currently, sunscreen is the most recommended agent for the prevention of SC. However, the growing incidence of this type of cancer has stressed the need for effective protective options complementary to sunscreen. In this work, we disclosed the promising activity of our recently identified reactivator of mutant p53 (mutp53), the compound SLMP53-2, as a preventive agent against SC. The pretreatment of human keratinocyte cells with SLMP53-2, prior to UVB exposure, led to a reduction in mutp53 levels with restoration of DNA-binding ability and subsequent transcriptional activity of the protein. Consistently, the pretreatment with SLMP53-2 increased the viability of irradiated cells by reducing apoptosis. The compound also protected cells from UVB-induced reactive oxygen species and subsequent oxidative damage. Treatment with SLMP53-2 also led to a marked reduction in radiation-induced DNA damage, and potentiated DNA repair via nucleotide excision repair pathway. SLMP53-2 also suppressed inflammation caused by UVB and promoted the expression of proteins involved in keratinocyte differentiation. Accordingly, the topical application of SLMP53-2 in mice skin, prior to UVB exposure, reduced cell death and DNA damage. It also decreased the expression of proteins associated with inflammation and promoted cell differentiation. Importantly, the compound did not induce cutaneous toxicity upon its cumulative topical use. With these results, SLMP53-2 emerges as a new encouraging chemopreventive agent against SC.

 

Authors and Affiliations:

Joana B. Loureiro a, Rita Ribeiro a, Nair Nazareth a, Tiago Ferreira b, Elizabeth A. Lopes c, Adelina Gama d, Miguel Machuqueiro e, Marco G. Alves f, Laura Marabini g, Paula A. Oliveira b, Maria M.M.Santos c, Lucília Saraiva a

LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-31b Porto, Portugal

Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal

Animal and Veterinary Research Centre (CECAV), Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences (ECAV), University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal

BioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal

Department of Anatomy and Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Portugal

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Italy

 

Abstract :

The growing incidence of skin cancer (SC) has prompted the search for additional preventive strategies to counteract this global health concern. Mutant p53 (mutp53), particularly with ultraviolet radiation (UVR) signature, has emerged as a promising target for SC prevention based on its key role in skin carcinogenesis. Herein, the preventive activity of our previously disclosed mutp53 reactivator SLMP53-2 against UVR-induced SC was investigated. The pre-treatment of keratinocyte HaCaT cells with SLMP53-2, before UVB exposure, depleted mutp53 protein levels with restoration of wild-type-like p53 DNA-binding ability and subsequent transcriptional activity. SLMP53-2 increased cell survival by promoting G1-phase cell cycle arrest, while reducing UVB-induced apoptosis through inhibition of c-Jun N-terminal kinase (JNK) activity. SLMP53-2 also protected cells from reactive oxygen species and oxidative damage induced by UVB. Moreover, it enhanced DNA repair through upregulation of nucleotide excision repair pathway and depletion of UVB-induced DNA damage, as evidenced by a reduction of DNA in comet tails, γH2AX staining and cyclobutane pyrimidine dimers (CPD) levels. SLMP53-2 further suppressed UVB-induced inflammation by inhibiting the nuclear translocation and DNA-binding ability of NF-κB, and promoted the expression of key players involved in keratinocytes differentiation. Consistently, the topical application of SLMP53-2 in mice skin, prior to UVB irradiation, reduced cell death and DNA damage. It also decreased the expression of inflammatory-related proteins and promoted cell differentiation, in UVB-exposed mice skin. Notably, SLMP53-2 did not show signs of skin toxicity for cumulative topical use. Overall, these results support a promising protective activity of SLMP53-2 against UVB-induced SC.

 

Journal: Pharmacological research

 

Link: https://www.sciencedirect.com/science/article/pii/S1043661821006101