Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition
Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MT...
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doaj-b065b246f1eb4854b82c81ce6951171a2020-11-25T02:20:44ZengMDPI AGInternational Journal of Molecular Sciences1422-00672020-01-0121268110.3390/ijms21020681ijms21020681Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II InhibitionJian-Ching Wu0Han-En Tsai1Yi-Hsiang Hsiao2Ji-Syuan Wu3Chieh-Shan Wu4Ming-Hong Tai5Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, TaiwanInstitute of Biomedical Science, National Sun Yat-sen University, Kaohsiung 80424, TaiwanInstitute of Biomedical Science, National Sun Yat-sen University, Kaohsiung 80424, TaiwanInstitute of Biomedical Science, National Sun Yat-sen University, Kaohsiung 80424, TaiwanDepartment of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung 81362, TaiwanDoctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, 70 Lien-Hai Road, Kaohsiung 80424, TaiwanMelanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MTII using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MTII potently inhibited the migration, invasion, and colony-forming capability of melanoma cells. Moreover, topical MTII application significantly attenuated the tumor progression in mice bearing established melanoma. Histological analysis revealed that MTII therapy induced apoptosis while inhibiting the proliferation and neovaluarization in melanoma tissues. By immunoblot and immunohistochemical analysis, it was found that MTII dose-dependently increased the phosphatase and tensin homolog (PTEN) protein level while reducing PTEN phosphorylation, which resulted in the inhibition of AKT/nuclear factor kappa B (NFκB) signaling. Consistently, MTII treatment inhibited cyclooxygenase II (COX-2) expression and prostaglandin E2 (PGE2) production in melanoma cells. Finally, studies of antibody neutralization suggest that the melanocortin 1 receptor (MC1R) plays a critical role in MTII-induced PTEN upregulation and melanoma suppression. Together, these results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling. Hence, topical MTII therapy may facilitate a novel therapeutic strategy against melanoma.https://www.mdpi.com/1422-0067/21/2/681mtiimelanomaptencox-2pge2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jian-Ching Wu Han-En Tsai Yi-Hsiang Hsiao Ji-Syuan Wu Chieh-Shan Wu Ming-Hong Tai |
spellingShingle |
Jian-Ching Wu Han-En Tsai Yi-Hsiang Hsiao Ji-Syuan Wu Chieh-Shan Wu Ming-Hong Tai Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition International Journal of Molecular Sciences mtii melanoma pten cox-2 pge2 |
author_facet |
Jian-Ching Wu Han-En Tsai Yi-Hsiang Hsiao Ji-Syuan Wu Chieh-Shan Wu Ming-Hong Tai |
author_sort |
Jian-Ching Wu |
title |
Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition |
title_short |
Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition |
title_full |
Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition |
title_fullStr |
Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition |
title_full_unstemmed |
Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition |
title_sort |
topical mtii therapy suppresses melanoma through pten upregulation and cyclooxygenase ii inhibition |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2020-01-01 |
description |
Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MTII using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MTII potently inhibited the migration, invasion, and colony-forming capability of melanoma cells. Moreover, topical MTII application significantly attenuated the tumor progression in mice bearing established melanoma. Histological analysis revealed that MTII therapy induced apoptosis while inhibiting the proliferation and neovaluarization in melanoma tissues. By immunoblot and immunohistochemical analysis, it was found that MTII dose-dependently increased the phosphatase and tensin homolog (PTEN) protein level while reducing PTEN phosphorylation, which resulted in the inhibition of AKT/nuclear factor kappa B (NFκB) signaling. Consistently, MTII treatment inhibited cyclooxygenase II (COX-2) expression and prostaglandin E2 (PGE2) production in melanoma cells. Finally, studies of antibody neutralization suggest that the melanocortin 1 receptor (MC1R) plays a critical role in MTII-induced PTEN upregulation and melanoma suppression. Together, these results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling. Hence, topical MTII therapy may facilitate a novel therapeutic strategy against melanoma. |
topic |
mtii melanoma pten cox-2 pge2 |
url |
https://www.mdpi.com/1422-0067/21/2/681 |
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