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New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function

Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy....

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Autores principales: Fu, Yuanyuan, Gu, Qianqian, Luo, Li, Xu, Jiecheng, Luo, Yuping, Xia, Fan, Han, Fanghai, Hong, Liang, Yin, Xiao-Ming, Huang, Zhiying, Li, Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352571/
https://www.ncbi.nlm.nih.gov/pubmed/32532053
http://dx.doi.org/10.3390/cancers12061523
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author Fu, Yuanyuan
Gu, Qianqian
Luo, Li
Xu, Jiecheng
Luo, Yuping
Xia, Fan
Han, Fanghai
Hong, Liang
Yin, Xiao-Ming
Huang, Zhiying
Li, Min
author_facet Fu, Yuanyuan
Gu, Qianqian
Luo, Li
Xu, Jiecheng
Luo, Yuping
Xia, Fan
Han, Fanghai
Hong, Liang
Yin, Xiao-Ming
Huang, Zhiying
Li, Min
author_sort Fu, Yuanyuan
collection PubMed
description Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although some inhibitors of either lysosome or ATG4B were reported, there are limitations in the use of these single target compounds. Considering multi-functional drugs have advantages, such as high efficacy and low toxicity, we first screened and validated a batch of compounds designed and synthesized in our laboratory by combining the screening method of ATG4B inhibitors and the identification method of lysosome inhibitors. ATG4B activity was effectively inhibited in vitro. Moreover, 163N inhibited autophagic flux and caused the accumulation of autolysosomes. Further studies demonstrated that 163N could not affect the autophagosome-lysosome fusion but could cause lysosome dysfunction. In addition, 163N diminished tumor cell viability and impaired the development of colorectal cancer in vivo. The current study findings indicate that the dual effect inhibitor 163N offers an attractive new anti-cancer drug and compounds having a combination of lysosome inhibition and ATG4B inhibition are a promising therapeutic strategy for colorectal cancer therapy.
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spelling pubmed-73525712020-07-15 New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function Fu, Yuanyuan Gu, Qianqian Luo, Li Xu, Jiecheng Luo, Yuping Xia, Fan Han, Fanghai Hong, Liang Yin, Xiao-Ming Huang, Zhiying Li, Min Cancers (Basel) Article Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although some inhibitors of either lysosome or ATG4B were reported, there are limitations in the use of these single target compounds. Considering multi-functional drugs have advantages, such as high efficacy and low toxicity, we first screened and validated a batch of compounds designed and synthesized in our laboratory by combining the screening method of ATG4B inhibitors and the identification method of lysosome inhibitors. ATG4B activity was effectively inhibited in vitro. Moreover, 163N inhibited autophagic flux and caused the accumulation of autolysosomes. Further studies demonstrated that 163N could not affect the autophagosome-lysosome fusion but could cause lysosome dysfunction. In addition, 163N diminished tumor cell viability and impaired the development of colorectal cancer in vivo. The current study findings indicate that the dual effect inhibitor 163N offers an attractive new anti-cancer drug and compounds having a combination of lysosome inhibition and ATG4B inhibition are a promising therapeutic strategy for colorectal cancer therapy. MDPI 2020-06-10 /pmc/articles/PMC7352571/ /pubmed/32532053 http://dx.doi.org/10.3390/cancers12061523 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fu, Yuanyuan
Gu, Qianqian
Luo, Li
Xu, Jiecheng
Luo, Yuping
Xia, Fan
Han, Fanghai
Hong, Liang
Yin, Xiao-Ming
Huang, Zhiying
Li, Min
New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function
title New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function
title_full New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function
title_fullStr New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function
title_full_unstemmed New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function
title_short New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function
title_sort new anti-cancer strategy to suppress colorectal cancer growth through inhibition of atg4b and lysosome function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352571/
https://www.ncbi.nlm.nih.gov/pubmed/32532053
http://dx.doi.org/10.3390/cancers12061523
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