FK506 positively regulates the migratory potential of melanocyte‐derived cells by enhancing syndecan‐2 expression

Abstract

Although topical tacrolimus (FK506) is known to promote repigmentation by increasing the pigmentation and migration of melanocytes, the mechanism through which FK506 regulates cell migration remains unclear. Here, we report that FK506 treatment enhanced cell spreading on laminin-332 and increased migration in both melanocytes and melanoma cells. Interestingly, FK506 also increased the expression of syndecan-2, a transmembrane heparan sulfate proteoglycan through c-jun terminal kinase activation. Moreover, siRNA-mediated reduction of syndecan-2 expression decreased FK506-mediated cell spreading and migration in melanoma cells and decreased focal adhesion kinase phosphorylation in both melanocytes and melanoma cells. Consistent with these effects on syndecan-2 expression, FK506 enhanced the membrane and melanosome localizations of PKCβII, a regulator of tyrosinase activity. This suggests that FK506 may play a dual regulatory role by affecting both melanogenesis and migration in melanocyte-derived cells. Interestingly, however, FK506 failed to show any synergistic effect on the migration of UVB-treated melanocyte-derived cells. Taken together, these data indicate that FK506 regulates cell migration by enhancing syndecan-2 expression, further suggesting that syndecan-2 could be a potential target for the treatment of patients with vitiligo.

Treatment Outcomes of Topical Calcineurin Inhibitor Therapy for Patients With Vitiligo

“…67 In in vivo studies, TCI treatment led to a decrease in tumor necrosis factor and an increase in IL-10 in vitiligo lesions. 8,13 Second, TCIs induce the repigmentation of vitiligo by stimulating melanocyte proliferation and migration 14,15,[17][18][19] and melanin synthesis. 14,15,19,20 This process involves increasing MMP-2 and MMP-9 activity, 17 increasing endothelin B receptor expression in melanoblasts, 16 and promoting the secretion of stem cell factor from keratinocytes following TCI treatment.…”

“…8,[13][14][15][16][17][18][19][20][21][22] First, TCIs downregulate proinflammatory cytokines, such as tumor necrosis factor, 8 and induce antiinflammatory cytokines, such as interleukin (IL)-10, in the vitiligo lesions. 13 Second, calcineurin inhibitors promote the migration and proliferation of melanocytes and melanoblasts 15,18,19 through increasing matrix metalloproteinase (MMP-2 and MMP-9) levels 17 and inducing endothelin B receptor expression in melanoblasts. 16 In an in vitro study, proliferation of melanocytes was significantly enhanced by tacrolimus-treated keratinocyte supernatant.…”

Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression

“…Thus, SDC2 was elevated in tissue samples from both nevus and malignant human melanomas in contrast to the normal melanocytes, and its expression was correlated with enhanced migration . Additionally, SDC2 regulated a calcineurin inhibitor‐tacrolimus (FK506)‐mediated melanoma cell migration through FAK activation . Tacrolimus was found to induce melanocyte migration and melanogenesis and increase SDC2 expression through JNK signalling .…”

“…Additionally, SDC2 regulated a calcineurin inhibitor‐tacrolimus (FK506)‐mediated melanoma cell migration through FAK activation . Tacrolimus was found to induce melanocyte migration and melanogenesis and increase SDC2 expression through JNK signalling .…”

Treatment Strategies for Hypopigmentation in the Context of Burn Hypertrophic Scars

“…FK506’s effect on human melanocytes was further investigated, demonstrating that total melanin levels increased when stimulated with FK506. 56 , 57 Jung and Oh 57 also demonstrated that FK506 promotes melanocyte maturation, increases melanin content and tyrosinase levels within melanocytes, and enhances keratinocyte uptake of melanosomes. Jung and Oh 57 used sucrose fractionation and pH sensitive dyes to separate and evaluate melanosomes by maturity to evaluate these end points.…”