Azithromycin, a potent autophagy inhibitor for cancer therapy, perturbs cytoskeletal protein dynamics
Menée à l'aide de lignées cellulaires de cancer du poumon, de myélome multiple et d'adénocarcinome surrénalien ainsi qu'à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'azithromycine inhibe l'autophagie des cellules cancéreuses en perturbant la dynamique des protéines du cytosquelette
Résumé en anglais
Background : Autophagy plays an important role in tumour cell growth and survival and also promotes resistance to chemotherapy. Hence, autophagy has been targeted for cancer therapy. We previously reported that macrolide antibiotics including azithromycin (AZM) inhibit autophagy in various types of cancer cells in vitro. However, the underlying molecular mechanism for autophagy inhibition remains unclear. Here, we aimed to identify the molecular target of AZM for inhibiting autophagy.
Methods : We identified the AZM-binding proteins using AZM-conjugated magnetic nanobeads for high-throughput affinity purification. Autophagy inhibitory mechanism of AZM was analysed by confocal microscopic and transmission electron microscopic observation. The anti-tumour effect with autophagy inhibition by oral AZM administration was assessed in the xenografted mice model.
Results : We elucidated that keratin-18 (KRT18) and