Sinomenine inhibits the growth of melanoma by enhancement of autophagy via PI3K/AKT/mTOR inhibition

BACKGROUND: Melanoma is a common skin tumor in adults with high metastasis and mortality rates. Thus, finding a better effective approach to treat melanoma has become very urgent. Sinomenine (SIN), the major active compound of Sinomenium acutum, has shown antitumorigenic activities in certain cancers. However, its role in melanoma remains unclear. PURPOSE: This study aimed to explore the effects of SIN on melanoma in vitro and in vivo, in addition to exploring the underlying mechanism. METHODS: Mouse melanoma cell B16-F10 treated by SIN was analyzed by CCK8 assay and flow cytometry. Melanoma xenograft model was then established by subcutaneously injection with B16-F10 cells. Tumor growth was measured by immunohistochemistry. To further investigate the relative mechanism, the autophagy and PI3K/Akt/mTOR pathway were examined by immunofluorescence and Western blot. RESULTS: Our results revealed that SIN dose dependently inhibited the proliferation of B16-F10 cells in vitro and attenuated melanoma growth in vivo. In addition, SIN treatment promoted the apoptosis of B16-F10 cells in a dose-dependent manner, as demonstrated by the increase in apoptotic cells, Bax/Bcl-2 ratio, and caspase-3 activity. Moreover, preconditioning with SIN dramatically enhanced autophagy activity by increasing Beclin-1 and LC3II/LC3I expression, in addition to decreasing p62 expression and augmenting the number of LC3 puncta, in B16-F10 cells. More importantly, autophagy inhibitor chloroquine partly abolished SIN’s effects on cell growth and apoptosis. Furthermore, our results showed that SIN-triggered activation of autophagy was mediated by PI3K/Akt/mTOR signaling pathway. CONCLUSION: Our study has identified a novel function of SIN and provided a molecular basis for potential applications of SIN in the treatment of melanoma and other cancers.