Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

Abstract

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.

PTEN as a target in melanoma

“…The findings above are supported by studies using synthetic analogue of α-MSH, Melanotan II (MTII), in a B16-F10 melanoma model 40. Treatment of B16-F10 cells using MTII significantly decreased levels of cellular migration and invasiveness.…”

“…The findings above are supported by studies using synthetic analogue of α-MSH, Melanotan II (MTII), in a B16-F10 melanoma model. 40 Treatment of B16-F10 cells using MTII significantly decreased levels of cellular migration and invasiveness. Similarly, in a B16-F10 murine model of primary melanoma, topical MTII treatment significantly reduced tumour sizes compared with control mice.…”

The Role of Prostaglandins in Different Types of Cancer

“…Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (alpha-MSH), potently inhibited the migration, invasion, and colony-forming capability of B16-F10 melanoma cells in vitro and in vivo despite a lack of influence on proliferation [40]. MTII treatment inhibited COX-2 expression and PGE 2 production via PTEN (fosfatidilinositol-3,4,5-trisfosfato 3-fosfatasa) upregulation, thereby suppressing melanoma progression.…”

Can Nimesulide Nanoparticles Be a Therapeutic Strategy for the Inhibition of the KRAS/PTEN Signaling Pathway in Pancreatic Cancer?

“…PTEN mutation and inactivation in pancreatic adenocarcinoma lead to hyperactivation of the PI3K/AKT pathway. AKT regulates a series of important effector proteins such as NF-kB (nuclear factor Kappa B), COX-2, VEGF, Bcl-2, and Bax which, when deregulated, lead to uncontrolled proliferation, survival, growth, and other cellular events such as inflammation, causing metastasis ( 16 , 66 ).…”

“…This growth factor is overexpressed in pancreatic cancer ( 16 ). PTEN reactivation appears to be related to decreased expression of COX-2, since overexpression of this isoform causes PTEN inactivation ( 15 , 16 , 66 ). In turn, PTEN also acts by suppressing AKT and consequently inhibiting NF-kB, which decreases the expression of COX-2 ( 15 , 68 , 69 ).…”