New anti-cancer strategy to suppress colorectal cancer growth through inhibition of atg4b and lysosome function

Yuanyuan Fu, Qianqian Gu, Li Luo, Jiecheng Xu, Yuping Luo, Fan Xia, Fanghai Han, Liang Hong, Xiao Ming Yin, Zhiying Huang, Min Li

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number1523
Pages (from-to)1-19
Number of pages19
JournalCancers
Volume12
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • ATG4B
  • Autophagy
  • Colorectal cancer
  • Dual-function inhibitor
  • Lysosome inhibition
  • New anti-cancer strategy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Fu, Y., Gu, Q., Luo, L., Xu, J., Luo, Y., Xia, F., Han, F., Hong, L., Yin, X. M., Huang, Z., & Li, M. (2020). New anti-cancer strategy to suppress colorectal cancer growth through inhibition of atg4b and lysosome function. Cancers, 12(6), 1-19. [1523]. https://doi.org/10.3390/cancers12061523