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

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Skin cancer (SC) incidence is rising globally, necessitating new preventive measures.
• Mutant p53 (mutp53), especially UVR-signature mutations, plays a critical role in skin carcinogenesis and is a potential target for prevention.

Purpose of the Study:

• To investigate the preventive efficacy of SLMP53-2, a novel mutp53 reactivator, against UVR-induced SC.
• To elucidate the molecular mechanisms underlying SLMP53-2's protective effects in skin cells and animal models.

Main Methods:

• Pre-treatment of keratinocyte HaCaT cells and topical application of SLMP53-2 in mice prior to UVB exposure.
• Assessment of p53 protein levels, DNA-binding ability, cell cycle, apoptosis, oxidative stress, DNA damage, inflammation, and differentiation markers.
• Evaluation of DNA repair pathways, including nucleotide excision repair, and inflammatory signaling pathways like NF-κB.

Main Results:

• SLMP53-2 depleted mutp53, restored wild-type p53 activity, promoted cell survival via G1 arrest, and reduced UVB-induced apoptosis by inhibiting JNK.
• The compound protected against oxidative stress, enhanced DNA repair (upregulating nucleotide excision repair), and reduced DNA damage markers (comet assay, γH2AX, CPDs).
• SLMP53-2 suppressed UVB-induced inflammation by inhibiting NF-κB and promoted keratinocyte differentiation. In mice, topical SLMP53-2 reduced cell death, DNA damage, and inflammation, with no observed toxicity.

Conclusions:

• SLMP53-2 demonstrates significant preventive activity against UVR-induced skin cancer in vitro and in vivo.
• Its mechanisms involve restoring p53 function, enhancing DNA repair, reducing oxidative stress and inflammation, and promoting keratinocyte differentiation.
• SLMP53-2 is a promising candidate for developing novel strategies for skin cancer prevention without apparent skin toxicity.