6-Azauridine Induces Autophagy-Mediated Cell Death via a p53- and AMPK-Dependent Pathway |
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Authors: | Yeo-Eun Cha Rackhyun Park Minsu Jang Yea-In Park Ayane Yamamoto Won Keun Oh Eun-Ju Lee Junsoo Park |
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Affiliation: | 1.Division of Biological Science and Technology, Yonsei University, Wonju 26493, Korea; (Y.-E.C.); (R.P.); (M.J.); (Y.-I.P.); (A.Y.);2.Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea;3.Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine, Seoul 06974, Korea; |
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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. |
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Keywords: | autophagy-mediated cell death 6-azauridine autophagy autophagic flux |
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