Azithromycin, a potent autophagy inhibitor for cancer therapy, perturbs cytoskeletal protein dynamics

Naoharu Takano, Masaki Hiramoto, Yumiko Yamada, Hiroko Kokuba, Mayumi Tokuhisa, Hirotsugu Hino, Keisuke Miyazawa

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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 α/β-tubulin specifically bind to AZM. Treatment of the cells with AZM disrupts intracellular KRT18 dynamics, and KRT18 knockdown resulted in autophagy inhibition. Additionally, AZM treatment suppresses intracellular lysosomal trafficking along the microtubules for blocking autophagic flux. Oral AZM administration suppressed tumour growth while inhibiting autophagy in tumour tissue. Conclusions: As drug-repurposing, our results indicate that AZM is a potent autophagy inhibitor for cancer treatment, which acts by directly interacting with cytoskeletal proteins and perturbing their dynamics.

Original languageEnglish
Pages (from-to)1838-1849
Number of pages12
JournalBritish Journal of Cancer
Volume128
Issue number10
DOIs
Publication statusPublished - 11 May 2023
Externally publishedYes

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