RESUMO
Previous evidence has shown that the increased expression of aurora kinase is closely related to melanoma progression and is an important therapeutic target in melanoma. Danusertib is an inhibitor of aurora kinase, and recent studies have shown that danusertib treatment induces autophagy in several types of cancer. Interestingly, autophagy plays a dual function in cancer as a pro-survival and anti-survival factor. In this study, we investigated the role of danusertib on the induction of autophagy in melanoma and determined the impact of autophagy induction on its anticancer activity against melanoma. Our results showed that danusertib can significantly inhibit melanoma growth by inducing cell cycle arrest and apoptosis. In addition, we demonstrated that danusertib treatment significantly inhibits the oncogenic Akt/mTOR signaling pathway and induces autophagy in melanoma cells. Furthermore, we identified that the inhibition of autophagy can enhance the inhibitory effects of danusertib on melanoma growth. Thus, the induction of autophagy by danusertib appears to be a survival mechanism in melanoma cells that may counteract its anticancer effects. These findings suggest a novel strategy to enhance the anticancer efficacy of danusertib in melanoma by blocking autophagy.
Assuntos
Benzamidas/administração & dosagem , Cloroquina/administração & dosagem , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Animais , Autofagia/efeitos dos fármacos , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Melanoma/metabolismo , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We investigated the efficacy of Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, in melanoma. We found that ALS exerts anti-proliferative, pro-apoptotic, and pro-autophagic effects on A375 and skmel-5 melanoma cells by inhibiting p38 MAPK signaling. SB202190, a p38 MAPK-selective inhibitor, enhanced ALS-induced apoptosis and autophagy in both cell lines. ALS induced cell cycle arrest in melanoma cells through activation of the p53/p21/cyclin B1 pathway. Knockdown of p38 MAPK enhanced ALS-induced apoptosis and reduced ALS-induced autophagy. Inhibition of autophagy sensitized melanoma cells to ALS-induced apoptosis. These data indicate ALS is a potential therapeutic agent for melanoma.
