1. G protein-coupled estrogen receptor enhances melanogenesis via cAMP-protein kinase (PKA) by upregulating microphthalmia-related transcription factor-tyrosinase in melanoma
- Author
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Yingxue Huang, Wei Shi, Yan Tang, Xinglin Hu, Hongfu Xie, Min Sun, Dan Jian, Shang-qing Lin, Shu-na Sun, and Jinmao Li
- Subjects
0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Tyrosinase ,Clinical Biochemistry ,Melanoma, Experimental ,Estrogen receptor ,Biochemistry ,Melanosis ,Receptors, G-Protein-Coupled ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Cyclic AMP ,Melanoma ,Skin ,integumentary system ,Pigmentation ,Microphthalmia-associated transcription factor ,Immunohistochemistry ,Up-Regulation ,Cell biology ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,Melanocytes ,Molecular Medicine ,Signal transduction ,GPER ,Signal Transduction ,medicine.medical_specialty ,Biology ,03 medical and health sciences ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Cyclic adenosine monophosphate ,Protein kinase A ,Molecular Biology ,Transcription factor ,Cell Proliferation ,Melanins ,Microphthalmia-Associated Transcription Factor ,Cell Biology ,Cyclic AMP-Dependent Protein Kinases ,030104 developmental biology ,Gene Expression Regulation ,chemistry - Abstract
Objective This study investigated the role and mechanism of action of G protein-coupled estrogen receptor (GPER) in melanogenesis. Methods GPER expression was detected in the A375 human melanoma cell line and B16 mouse melanoma cell line. Cell proliferation, melanin content, tyrosinase (TYR) activity, cyclic adenosine monophosphate (cAMP) level, and TYR and microphthalmia-related transcription factor (MITF) expression were measured. GPER activation was altered by agonist and antagonist treatment and its expression was downregulated by gene silencing. Estradiol-induced melanin synthesis and the activation of related signaling pathways were suppressed by inhibiting GPER via antagonist treatment. The relationship between GPER and TYR was evaluated in clinical chloasma samples by immunohistochemistry. Results Upregulation of GPER in A375 cells promoted melanogenesis, favored as indicated by increases in TYR and MITF expression and TYR activity. GPER activated melanin production via the cAMP-protein kinase (PK) A pathway, suggesting that GPER plays an important role in estrogen-induced melanin synthesis. The effect of GPER activation on cAMP-MITF-TYR signaling was also demonstrated in B16 cells. A significant association was observed between GPER and TYR expression in chloasma skin lesions relative to normal skin. Conclusion GPER enhances melanin synthesis via cAMP-PKA-MITF-TYR signaling and modulates the effects of estrogen in melanogenesis. GPER is therefore a potential drug target for chloasma treatment.
- Published
- 2017