Resveratrol Inhibits Alpha-Melanocyte-Stimulating Hormone Signaling, Viability, and Invasiveness in Melanoma Cells

Abstract

Melanoma is a malignancy with high potential to invasion and treatment resistance. The α-melanocyte-stimulating hormone (α-MSH) signal transduction involving Wnt/β-catenin, c-Kit, and microphthalmia-associated transcription factor (MITF), a known pathway to produce melanin, has been demonstrated as one of cancer stem cell characteristics. This study was aimed to examine the effect of resveratrol, an abundant ingredient of grape and medicinal plants, on α-MSH signaling, viability, and invasiveness in melanoma cells. By α-MSH treatment, the melanin production in B16 melanoma cells was augmented as a validation for activation of α-MSH signaling. The upregulated expression of α-MSH signaling-related molecules β-catenin, c-Kit, and MITF was suppressed by resveratrol and/or STI571 treatment. Nuclear translocation of MITF, a hallmark of α-MSH signaling activation, was inhibited by combined treatment of resveratrol and STI571. At effective concentration, resveratrol and/or STI571 inhibited cell viability and α-MSH-activated matrix metalloproteinase- (MMP-)9 expression and invasion capacity of B16 melanoma cells. In conclusion, resveratrol enhances STI571 effect on suppressing the α-MSH signaling, viability, and invasiveness in melanoma cells. It implicates that resveratrol may have potential to modulate the cancer stem cell characteristics of melanoma.

Phytochemicals for the Management of Melanoma

“…This lead to significantly prolonged animal survival time and reduced melanoma tumor sizes in vivo . This was associated with inhibition of lipopolysaccharide induced tumor migration and decreased markers of EMT [159, 163]. These data support a potential use of mono or combination resveratrol therapy for the management of melanoma.…”

“…Furthermore, upregulation of the α-melanocyte-stimulating hormone (α-MSH) signal transduction pathway involving Wnt/β-catenin, c-kit, and MITF were suppressed by resveratrol [158]. These signaling pathways have well-established roles in the immortality, viability, and invasiveness of melanoma cells [159]. In addition, Lee et al [160] found that resveratrol inhibited STAT3 acetylation, which is markedly increased in melanoma cells when compared to normal melanocytes.…”

“…In addition, Lee et al [160] found that resveratrol inhibited STAT3 acetylation, which is markedly increased in melanoma cells when compared to normal melanocytes. Inactivation of the estrogen receptor alpha (ERα) gene via methylation strongly correlates with poor prognosis as well as an aggressive phenotype of melanoma [159]. Resveratrol reactivates gene expression in tumors by reducing STAT3 acetylation [158].…”

“…Resveratrol has demonstrated its potential to inhibit melanoma growth by targeting various signaling pathways [153–157, 159, 171]. Murias et al [172, 173] synthesized resveratrol derivatives by increasing the number of hydroxyl groups on the phenol rings of the stilbene structure and evaluated their anti-tumor potential against human cancer cell lines.…”

Use of Polyphenolic Compounds in Dermatologic Oncology

“…Subsequently, cytochrome C, and caspase-9 and -3 are released [227, 228]. Furthermore, apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1), a protein enrolled in tumorigenesis, is inhibited [226, 229], resulting in a coordinated decrease in AP-1/JunD protein, MMP-1 and inducible NO (iNO) protein levels [226]. It reduces tumor invasiveness by inhibition of α-melanocyte-stimulating hormone (α-MSH) expression [230].…”