Abstract
6-Azauridine (6-AZA), a pyrimidine nucleoside analogue, is known to exhibit both antitumor and antiviral activities. Although 6-AZA was discovered more than 60 years ago, the cellular effects of this compound are yet to be elucidated. Here, we report that 6-AZA regulates autophagy-mediated cell death in various human cancer cells, where 6-AZA treatment activates autophagic flux through the activation of lysosomal function. Furthermore, 6-AZA exhibited cytotoxicity in all cancer cells studied, although the mechanisms of action were diverse. In H460 cells, 6-AZA treatment induced apoptosis, and the extent of the latter could be reduced by treatment with chloroquine (CQ), a lysosomal inhibitor. However, 6-AZA treatment resulted in cell cycle arrest in H1299 cells, which could not be reversed by CQ. The cytotoxicity associated with 6-AZA treatment could be linearly correlated to the degree of autophagy-mediated cell death. In addition, we demonstrated that the cytotoxic effect of 6-AZA was dependent on AMPK and p53. These results collectively indicate that autophagy-mediated cell death triggered by 6-AZA contributes to its antitumor effect.
Highlights
We further found that differential levels of autophagy-mediated cell death and 6-AZA cytotoxicity in various cancer cell lines are partly dependent on the presence of p53 and AMPK
We demonstrate that 6-AZA induces autophagy and decreases cell viability in cancer cells
We examined various cancer cells and found that the effect of 6-AZA is diverse in different cancer cells
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Treatment with chloroquine (CQ), an autophagic flux inhibitor, often leads to increased cell death by suppressing the protective role of autophagy in cellular physiology [7]. Autophagyassociated cell death is characterized by autophagy induction, along with apoptosis activation, where autophagy is not involved in cell death. Autophagy-mediated cell death is the induction of cell death, including apoptosis, which is dependent on autophagy activation [8]. We report that 6-AZA treatment induces autophagy and reduces cell viability. Since CQ blocks autophagic flux, we assumed that CQ-induced reduction in cytotoxicity represents autophagy-mediated cell death. We further found that differential levels of autophagy-mediated cell death and 6-AZA cytotoxicity in various cancer cell lines are partly dependent on the presence of p53 and AMPK
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