A Derivative Of Lipopeptide From Staphylococcus Epidermidis Regulates Melanoma Cells Proliferation, Differentiation And Metastasis

Melanoma, originated from melanocytes, is one of the most dangerous malignant tumors. Traditional treatments such as surgery, chemotherapy and radiation therapy cannot solve the problem of melanoma metastasis and recurrence. Therefore, targeted therapy and immunotherapy have become the major direction. Currently, inhibitors targeting the proto-oncogenes such as BRAF, MEK, etc are most commonly used in melanoma clinical treatment. However, long-term use of these inhibitors leads to drug resistance of cancer cells and some side effects, which makes them limited in melanoma treatment. This is also why people become more interested in looking for some natural compounds that could be used for cancer therapy.Lipopeptides are secondary metabolites of microorganisms, with a wide range of biological activities including anti-inflammation, bactericidal activity, anti-tumor, etc. Our laboratory has identified one lipopeptide from Staphylococcus epidermidis, one of skin commensal bacteria. This lipopeptide induces antibacterial peptides in keratinocytes against S.aureus infection. Furthermore, its derivative, LP78, could inhibit excessive wound inflammation, indicating that lipopeptides from skin commensals play important role in the host innate immune responses.In this study we found that a derivative of the lipopeptide from Staphylococcus epidermidis, named LP79, inhibited the proliferation of melanoma cell B16F10, inducing G1 phase cell cycle arrest, which was demonstrated by clonogenic assay and FACS.In addition to inhibiting the proliferaton, LP79 significantly inhibited the migration of B16F10 cells by in vitro scratching and Transwell assays. LP79 exerted this inhibitory function via the induction of MKP1 (Dual-specificity phosphatase 1) to inhibit N-Cadherin and Vimentin, both of which favor EMT. In vivo experimental tumor metastasis model further confirmed that LP79 significantly inhibited melanoma metastasis to lung. Furthermore, LP79 induced B16F10 differentiation via the induction of TRP1 (Tyrosinase-related protein 1), but this was not related to the inhibitory effect of LP79 on melanoma migration. Althoguh Toll-like receptor (TLR)-2 has been suggested as a receptor for lipopeptide, it did not involve in the inhibition of melanoma migration by LP79.Taken together, our study demonstrates that the derivative of lipopeptide from Staphylococcus epidermidis, LP79, has the bioactivity of inhibiting melanoma migration. Our findings also provide new insights into the development of new drugs for melanoma, and potential therapeutic strategies for treatment of melanoma.