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.

VDAC1 negatively regulates melanogenesis through the Ca2+-calcineurin-CRTC1-MITF pathway

“…To explore how MITF is up-regulated upon VDAC1 knockdown, the phosphorylated-CREB (p-CREB) and CRTC1, which are important for the transduction of the cAMP signal to induce the transcription of MITF, were examined ( Kim et al, 2019 ). p-CREB and CRTC1 were detected by Western blotting after nuclear and cytoplasmic proteins were isolated in MNT1 cells.…”

Carvedilol, an Adrenergic Blocker, Suppresses Melanin Synthesis by Inhibiting the cAMP/CREB Signaling Pathway in Human Melanocytes and Ex Vivo Human Skin Culture

“…However, the anti-melanogenesis mechanisms of the specific agents are currently uncertain and have generally been evaluated in mouse cells, which yield results that are not always consistent with those of human skin trials [27,28]. Moreover, as the melanogenesis of melanocytes is tightly regulated by keratinocytes and other neighboring cells, cocultured human cells or ex vivo human skin are more reliable experimental settings for the exploration of effective whitening agents [29]. Most skin whitening agents, whether naturally or chemically derived, may cause skin toxicity or irritation, which can be predicted to a certain extent using in vitro cellular viability assays with melanocytes.…”

“…In addition, to develop safe whitening agents, reliable and reproducible mechanisms of anti-melanogenesis should be pursued in parallel. The most physiologically significant stimulus is UV, and among UVR signaling to epidermal melanocytes, the CREB axis is the most established pathway for the regulation of melanogenesis in the human epidermis [29]. Exposure to UV successively activates cAMP production, PKA, and the transcription factor CREB, which, in turn, induces the expression of MITF and downstream target melanogenic genes [38,39].…”

BCI-215, a Dual-Specificity Phosphatase Inhibitor, Reduces UVB-Induced Pigmentation in Human Skin by Activating Mitogen-Activated Protein Kinase Pathways

“…Several whitening agents have been developed, but their general application has been limited due to their instability and irritability as well as safety concerns. Moreover, the effects of the individual ingredients of currently available products of this nature remain problematic despite numerous testings of different compounds [ 1 , 2 ]. Hence, the development of a whitening agent that is effective and safe is still an unmet need as part of an efficient and affordable treatment regimen for hyperpigmentation [ 3 ].…”