Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo

Yuanyuan Fu, Liang Hong, Jiecheng Xu, Guoping Zhong, Qiong Gu, Qianqian Gu, Yanping Guan, Xueping Zheng, Qi Dai, Xia Luo, Cui Liu, Zhiying Huang, Xiao Ming Yin, Peiqing Liu, Min Li

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Human Atg4 homologs are cysteine proteases, which play key roles in the macroautophagy/autophagy process by cleaving Atg8 homologs for conjugation to lipid membranes and for deconjugation of Atg8 homologs from membranes. Expression of ATG4B is significantly increased in colorectal cancer cells compared to normal cells, suggesting that ATG4B may be important for cancer biology. Inhibition of ATG4B may reduce the autophagy activity, thereby sensitizing cancer cells to therapeutic agents. Thus, developing specific and potent ATG4B inhibitors for research as well as for potential therapeutic uses is highly needed. In this study, we integrated in silico screening and in vitro assays to discover a potent ATG4B inhibitor, named S130, from a noncommercial library. This chemical binds to ATG4B with strong affinity and specifically suppresses the activity of ATG4B but not other proteases. S130 did not cause the impairment of autophagosome fusion, nor did it result in the dysfunction of lysosomes. Instead, S130 might attenuate the delipidation of LC3-II on the autolysosomes to suppress the recycling of LC3-I, which normally occurs after LC3-II cleavage by ATG4B. Intriguingly, S130 induced cell death, which was accompanied with autophagy stress and could be further exacerbated by nutrient deprivation. Such cytotoxicity could be partially reversed by enhancing ATG4B activity. Finally, we found that S130 was distributed in tumor tissues in vivo and was also effective in arresting the growth of colorectal cancer cells. Thus, this study indicates that ATG4B is a potential anticancer target and S130 might be a novel small-molecule candidate for future cancer therapy.

Original languageEnglish (US)
Pages (from-to)295-311
Number of pages17
JournalAutophagy
Volume15
Issue number2
DOIs
StatePublished - Feb 1 2019

Keywords

  • ATG4B
  • Anti-tumor
  • FRET assay
  • autophagy
  • cell death
  • colorectal cancer
  • delipidation
  • xenografts

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo'. Together they form a unique fingerprint.

  • Cite this

    Fu, Y., Hong, L., Xu, J., Zhong, G., Gu, Q., Gu, Q., Guan, Y., Zheng, X., Dai, Q., Luo, X., Liu, C., Huang, Z., Yin, X. M., Liu, P., & Li, M. (2019). Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo. Autophagy, 15(2), 295-311. https://doi.org/10.1080/15548627.2018.1517073