Mutant p53 reactivator SLMP53-2 hinders ultraviolet B radiation-induced skin carcinogenesis. (January 2022)

• Record Type: Journal Article
• Authors: Loureiro, Joana B.; Ribeiro, Rita; Nazareth, Nair; Ferreira, Tiago; Lopes, Elizabeth A.; Gama, Adelina; Machuqueiro, Miguel; Alves, Marco G.; Marabini, Laura; Oliveira, Paula A.; Santos, Maria M.M.; Saraiva, Lucília
• Is Part Of: Pharmacological research. Volume 175(2022)
• Publication Date: 2022-01
• Subjects: 6-4PP Pyrimidine (6-4) pyrimidone photoproducts -- BCC Basal cell carcinoma -- CPD Cyclobutane pyrimidine dimers -- JNK c-Jun N-terminal kinase -- MAPK Mitogen-activated protein kinase -- MDM2 Mouse double minute 2 -- Mutp53 Mutant p53 -- NER Nucleotide excision repair -- NF-κB Nuclear factor kappa B -- NMSC Non-melanoma skin cancer -- PCNA Proliferating cell nuclear antigen -- PTEN Phosphatase and tensin homolog -- ROS Reactive oxygen species -- SC Skin cancer -- SCC Squamous cell carcinoma -- UVB Ultraviolet B -- UVR Ultraviolet radiation -- Wt Wild-type; Chemoprevention -- p53 -- Skin cancer -- UVB radiation -- Tryptophanol-derived oxazoloisoindolinone; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.106026
• Languages: English
• ISSNs: 1043-6618

Abstract

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. Graphical Abstract: ga1