Therapeutic Potential of Rottlerin for Skin Hyperpigmentary Disorders by Inhibiting the Transcriptional Activity of CREB-Regulated Transcription Coactivators

Abstract

Exposure to UVR stimulates the cAMP signaling pathway, which leads to melanin deposits in skin tissues. Although melanogenesis can be beneficial by protecting skin from UVR-induced damage, excessive or uneven deposits of melanin can cause various skin hyperpigmentation disorders. Because cAMP-responsive element binding protein (CREB) and CREB-regulated transcription coactivators (CRTC) play a major role in conveying cAMP signals that induce transcription of microphthalmia-associated transcription factor and melanin production, we screened for a CREB or CRTC inhibitor and identified rottlerin (Rot) as a potent inhibitor of its transcriptional activity. Rot suppressed melanin production in both basal and cAMP-stimulated cultured melanocytes by downregulating melanogenic gene expression. In addition, topical application of Rot on the tails of mice decreased melanin accumulation. Mechanistically, we showed that Rot decreased the mitochondrial membrane potential, which then activated AMPK, leading to the phosphorylation and nuclear exclusion of CRTC3 and suppressing the expression of CREB target genes, including MITF. Our study demonstrates that Rot is an active antimelanogenic agent and suggests that screening for an inhibitor of CREB or CRTC transcriptional activity is a promising strategy by which to discover better drugs to treat skin hyperpigmentary disorders.