2. Academic Validation
  3. Mutant p53 reactivator SLMP53-2 hinders ultraviolet B radiation-induced skin carcinogenesis

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

  • Pharmacol Res. 2022 Jan;175:106026. doi: 10.1016/j.phrs.2021.106026.
Joana B Loureiro 1,  Rita Ribeiro 1,  Nair Nazareth 1,  Tiago Ferreira 2,  Elizabeth A Lopes 3,  Adelina Gama 4,  Miguel Machuqueiro 5,  Marco G Alves 6,  Laura Marabini 7,  Paula A Oliveira 2,  Maria M M Santos 3,  Lucília Saraiva 8
Affiliations

Affiliations

  • 1 LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-31b Porto, Portugal.
  • 2 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.
  • 3 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
  • 4 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.
  • 5 BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal.
  • 6 Department of Anatomy and Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Portugal.
  • 7 Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Italy.
  • 8 LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-31b Porto, Portugal. Electronic address: lucilia.saraiva@ff.up.pt.
PMID: 34890775 DOI: 10.1016/j.phrs.2021.106026
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.

Keywords

Chemoprevention; Skin cancer; Tryptophanol-derived oxazoloisoindolinone; UVB radiation; p53.

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