Autophagy inhibition potentiates the anti-EMT effects of alteronol through TGF-β/Smad3 signaling in melanoma cells

Accumulating evidence demonstrated that alteronol, a novel compound that has a similar structure with paclitaxel, exerts anticancer effects against diversified tumors. However, whether alteronol induces autophagy and the relationship between its anticancer effects and autophagy in melanoma remains elusive. In this study, we show that alteronol induces not only anti-proliferation activity and apoptosis but also autophagy in A375 and UACC62 cells. In addition, alteronol inhibits A375 and UACC62 cells invasion and migration by preventing the epithelial-mesenchymal transition (EMT). Blocking autophagy enhances alteronol-induced apoptosis and anti-EMT effects in vitro and in vivo. Mechanistically, we find that alteronol significantly inhibits Akt/mTOR and TGFβ/Smad3 pathways, and co-treatment with autophagy inhibitor 3-MA further potentiate these effects. Our results suggest that alteronol induces cyto-protective autophagy in melanoma cells through inhibition of Akt/mTOR pathway, thus attenuates apoptosis and promotes melanoma cell EMT through TGF-β/Smad3 pathway. Combination with alteronol and autophagy inhibitor 3-MA may be a potential treatment for melanoma as it not only significantly inhibited tumor growth but also suppressed tumor invasion and migration as anti-metastasis agent.