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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| Format: | Article |
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MDPI AG
2020-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/6/1523 |
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| author | Yuanyuan Fu Qianqian Gu Li Luo Jiecheng Xu Yuping Luo Fan Xia Fanghai Han Liang Hong Xiao-Ming Yin Zhiying Huang Min Li |
| author_facet | Yuanyuan Fu Qianqian Gu Li Luo Jiecheng Xu Yuping Luo Fan Xia Fanghai Han Liang Hong Xiao-Ming Yin Zhiying Huang Min Li |
| author_sort | Yuanyuan Fu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T19:15:20Z |
| format | Article |
| id | doaj.art-bd976d6235994b3a98f1b785d4d2baeb |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:15:20Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-bd976d6235994b3a98f1b785d4d2baeb2023-11-20T03:27:07ZengMDPI AGCancers2072-66942020-06-01126152310.3390/cancers12061523New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome FunctionYuanyuan Fu0Qianqian Gu1Li Luo2Jiecheng Xu3Yuping Luo4Fan Xia5Fanghai Han6Liang Hong7Xiao-Ming Yin8Zhiying Huang9Min Li10School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaDepartment of Gastrointestinal Surgery, Sun Yat-sen University, Guangzhou 510120, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaDepartment of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USASchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaAutophagy 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.https://www.mdpi.com/2072-6694/12/6/1523ATG4Bautophagycolorectal cancerdual-function inhibitorlysosome inhibitionnew anti-cancer strategy |
| spellingShingle | Yuanyuan Fu Qianqian Gu Li Luo Jiecheng Xu Yuping Luo Fan Xia Fanghai Han Liang Hong Xiao-Ming Yin Zhiying Huang Min Li New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function Cancers ATG4B autophagy colorectal cancer dual-function inhibitor lysosome inhibition new anti-cancer strategy |
| 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 | ATG4B autophagy colorectal cancer dual-function inhibitor lysosome inhibition new anti-cancer strategy |
| url | https://www.mdpi.com/2072-6694/12/6/1523 |
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