Imidazole inhibits autophagy flux by blocking autophagic degradation and triggers apoptosis via increasing FoxO3a-Bim expression

Liu,Zhenxing; Wang,Yingzheng; Zhao,Shuan; Zhang,Jingyou; Wu,Yi; Zeng,Shenming

doi:10.3892/ijo.2014.2771

Imidazole inhibits autophagy flux by blocking autophagic degradation and triggers apoptosis via increasing FoxO3a-Bim expression

Authors:
- Zhenxing Liu
- Yingzheng Wang
- Shuan Zhao
- Jingyou Zhang
- Yi Wu
- Shenming Zeng
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Affiliations: Laboratory of Animal Embryonic Biotechnology, College of Animal Science and Technology, China Agricultural University, Beijing 100193, P.R. China, Reproduction and Breeding Research Center, Animal Husbandry and Veterinary 9th Research Institute, Heilongjiang Academy of Agricultural and Reclamation Science, Harbin 150006, P.R. China
Published online on: November 21, 2014 https://doi.org/10.3892/ijo.2014.2771
Pages: 721-731

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Abstract

Imidazole, an organic alkaloid, is an important pharmacophore in drug discovery. Anti-neoplastic potential of imidazole derivatives has been documented in several studies; however, mechanisms by which tumor cells respond to these stimuli remain to be elucidated. Autophagy and apoptosis have key roles in tumorigenesis and tumor treatment. In this study, we systematically examined autophagic events induced by imidazole in HEC‑1B cells. Accumulation of autophagic vacuoles in imidazole-treated cells was verified by conversion of LC3 protein, as well as confocal and transmission electron microscopy. Furthermore, imidazole blocked autophagic degradation by impairing maturation of autophagosomes into autolysosomes. Concurrently, imidazole treatment induced apoptosis in HEC‑1B cells, accompanied by activation of caspase 9 and 3. The proapoptotic effect was mediated by increased Bim expression. Moreover, imidazole upregulated the protein level of Foxo3a and induced its increased nuclear localisation. In addition, siRNA-mediated silencing of FoxO3a effectively attenuated imidazole-induced Bim upregulation and cell death, indicating direct involvement of this pathway in the imidazole-induced apoptosis. Taken together, our data provided a molecular link between imidazoles and anticancer therapies; understanding of these properties of imidazole is essential for development of effective cancer therapeutics using imidazoles.

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