Skin cancer (SC) is one of the most common cancers in fair-skinned population. To counteract this public health concern, additional preventive approaches to sunscreen is needed. Mutant p53 (mutp53) is an appealing target for SC prevention given its crucial role in ultraviolet B (UVB) radiation-induced skin carcinogenesis. Therefore, the reduction of mutp53 protein levels by its reactivation would constitute a valuable preventive strategy. Herein, we investigated the potential of our recently identified mutp53 reactivator SLMP53-2, as a SC chemopreventive agent. The SLMP53-2 pre-treatment of keratinocyte HaCaT cells, before UVB exposure, reduced mutp53 protein levels with restoration of its wild-type-like p53 activity. Subsequently, SLMP53-2 pre-treatment increased cell survival, by promoting G1-phase cell cycle arrest, while reducing UVB-induced apoptosis through inhibition of c-Jun N-terminal kinase activity. UVB-induced reactive oxygen species and oxidative damages were also reduced by SLMP53-2. Furthermore, it protected from UVB-induced DNA damage, through increased DNA repair via nucleotide excision repair pathway. Also, by decreasing the nuclear translocation and DNA binding ability of NF-κB, it reverted UVB-induced inflammation, and stimulated the expression of keratinocytes differentiation markers. Consistently, the topical application of SLMP53-2 in mice, previous to UVB irradiation, also inhibited cell death, DNA damage and expression of inflammatory-related proteins, while promoting cell differentiation, without displaying signs of skin toxicity. Collectively, the results reveal a promising application of SLMP53-2 in UVB-induced SC prevention.

Acknowledgements: FCT/MCTES for the projects UIDB/50006/2020, PTDC/QUI-QOR/1304/2020, SFRH/BD/128673/2017, SFRH/BD/137544/2018.