Abstract
Hsp90 is a potential therapeutic target for tumor, as it maintains the stability of a variety of proteins related to tumor development and progression. Autophagy is a self-degradation process to maintain cellular homeostasis and autophagy inhibitors can suppress tumor growth. In this study, we identified DCZ5248, a triazine derivative, was a dual inhibitor of both Hsp90 and late-autophagy with potent antitumor activity against colon cancer cells in vitro and in vivo. We showed that DCZ5248 (0.1–10 μM) induced dose-dependent degradation of Hsp90 client proteins (AKT, CDK4, CDK6 and RAF-1) in HCT 116 colon cancer cells through a proteasome-dependent pathway. Meanwhile, DCZ5248 (0.3 μM) induced cytoplasmic vacuole formation, LC3 II conversion, p62 protein upregulation, and inhibited autophagy at the late stage in the colon cancer cell lines tested. We further revealed that the inhibition of autophagy was achieved by impairing lysosomal functions through induction of lysosomal acidification and attenuation of lysosomal cathepsin activity. The modulation of autophagy by DCZ5248 was independent of Hsp90 inhibition as the autophagy inhibition was not blocked by Hsp90 knockdown. Importantly, inhibition of both Hsp90 function and autophagy by DCZ5248 induced G1-phase cell cycle arrest, apoptosis, and exerted potent antitumor activity against colon cancer cells both in vitro and in vivo. These findings demonstrate that DCZ5248 is a novel dual inhibitor of Hsp90 and autophagy with potential for colon cancer therapy.
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27 November 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41401-023-01184-6
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Acknowledgements
This research was supported by grants from the National Natural Science Foundation of China (No. 81273546), the Science and Technology Commission of Shanghai Municipality (No. 18DZ2293200) and the Yunnan Province Sciences and Technology plan (No. 2017ZF010).
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LGL and WLZ conceived the project; XLC wrote the manuscript, performed the experiments, and analyzed the data; PL synthesized the compound DCZ5248.
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The original online version of this article was revised: Western blot images of Atg12 in Fig. 2a and GAPDH in Fig.4d was inadvertently misplaced in the process of assembling figures.
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Chen, Xl., Liu, P., Zhu, Wl. et al. DCZ5248, a novel dual inhibitor of Hsp90 and autophagy, exerts antitumor activity against colon cancer. Acta Pharmacol Sin 42, 132–141 (2021). https://doi.org/10.1038/s41401-020-0398-2
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DOI: https://doi.org/10.1038/s41401-020-0398-2
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