AMDE-1 is a dual function chemical for autophagy activation and inhibition

Min Li, Zuolong Yang, Laura L. Vollmer, Ying Gao, Yuanyuan Fu, Cui Liu, Xiaoyun Chen, Peiqing Liu, Andreas Vogt, Xiao-Ming Yin

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Autophagy is the process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy plays important roles in cellular homeostasis and disease pathogenesis. Small chemical molecules that can modulate autophagy activity may have pharmacological value for treating diseases. Using a GFP-LC3-based high content screening assay we identified a novel chemical that is able to modulate autophagy at both initiation and degradation levels. This molecule, termed as Autophagy Modulator with Dual Effect-1 (AMDE-1), triggered autophagy in an Atg5-dependent manner, recruiting Atg16 to the pre-autophagosomal site and causing LC3 lipidation. AMDE-1 induced autophagy through the activation of AMPK, which inactivated mTORC1 and activated ULK1. AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction. Surprisingly, treatment with AMDE-1 resulted in impairment in autophagic flux and inhibition of long-lived protein degradation. This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion. Further analysis indicated that AMDE-1 caused a reduction in lysosome acidity and lysosomal proteolytic activity, suggesting that it suppressed general lysosome function. AMDE-1 thus also impaired endocytosis-mediated EGF receptor degradation. The dual effects of AMDE-1 on autophagy induction and lysosomal degradation suggested that its net effect would likely lead to autophagic stress and lysosome dysfunction, and therefore cell death. Indeed, AMDE-1 triggered necroptosis and was preferentially cytotoxic to cancer cells. In conclusion, this study identified a new class of autophagy modulators with dual effects, which can be explored for potential uses in cancer therapy.

Original languageEnglish
Article numbere0122083
JournalPLoS One
Volume10
Issue number4
DOIs
StatePublished - Apr 20 2015

Fingerprint

autophagy
Autophagy
Modulators
Chemical activation
Degradation
lysosomes
Lysosomes
degradation
MAP Kinase Kinase 4
AMP-Activated Protein Kinases
Molecules
Oxidative stress
Cell death
mitogen-activated protein kinase
Epidermal Growth Factor Receptor
Acidity
Assays
Screening
Fusion reactions
Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

AMDE-1 is a dual function chemical for autophagy activation and inhibition. / Li, Min; Yang, Zuolong; Vollmer, Laura L.; Gao, Ying; Fu, Yuanyuan; Liu, Cui; Chen, Xiaoyun; Liu, Peiqing; Vogt, Andreas; Yin, Xiao-Ming.

In: PLoS One, Vol. 10, No. 4, e0122083, 20.04.2015.

Research output: Contribution to journalArticle

Li, M, Yang, Z, Vollmer, LL, Gao, Y, Fu, Y, Liu, C, Chen, X, Liu, P, Vogt, A & Yin, X-M 2015, 'AMDE-1 is a dual function chemical for autophagy activation and inhibition', PLoS One, vol. 10, no. 4, e0122083. https://doi.org/10.1371/journal.pone.0122083
Li M, Yang Z, Vollmer LL, Gao Y, Fu Y, Liu C et al. AMDE-1 is a dual function chemical for autophagy activation and inhibition. PLoS One. 2015 Apr 20;10(4). e0122083. https://doi.org/10.1371/journal.pone.0122083
Li, Min ; Yang, Zuolong ; Vollmer, Laura L. ; Gao, Ying ; Fu, Yuanyuan ; Liu, Cui ; Chen, Xiaoyun ; Liu, Peiqing ; Vogt, Andreas ; Yin, Xiao-Ming. / AMDE-1 is a dual function chemical for autophagy activation and inhibition. In: PLoS One. 2015 ; Vol. 10, No. 4.
@article{de84ec9eaa7c4b6ea935de375a576ffc,
title = "AMDE-1 is a dual function chemical for autophagy activation and inhibition",
abstract = "Autophagy is the process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy plays important roles in cellular homeostasis and disease pathogenesis. Small chemical molecules that can modulate autophagy activity may have pharmacological value for treating diseases. Using a GFP-LC3-based high content screening assay we identified a novel chemical that is able to modulate autophagy at both initiation and degradation levels. This molecule, termed as Autophagy Modulator with Dual Effect-1 (AMDE-1), triggered autophagy in an Atg5-dependent manner, recruiting Atg16 to the pre-autophagosomal site and causing LC3 lipidation. AMDE-1 induced autophagy through the activation of AMPK, which inactivated mTORC1 and activated ULK1. AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction. Surprisingly, treatment with AMDE-1 resulted in impairment in autophagic flux and inhibition of long-lived protein degradation. This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion. Further analysis indicated that AMDE-1 caused a reduction in lysosome acidity and lysosomal proteolytic activity, suggesting that it suppressed general lysosome function. AMDE-1 thus also impaired endocytosis-mediated EGF receptor degradation. The dual effects of AMDE-1 on autophagy induction and lysosomal degradation suggested that its net effect would likely lead to autophagic stress and lysosome dysfunction, and therefore cell death. Indeed, AMDE-1 triggered necroptosis and was preferentially cytotoxic to cancer cells. In conclusion, this study identified a new class of autophagy modulators with dual effects, which can be explored for potential uses in cancer therapy.",
author = "Min Li and Zuolong Yang and Vollmer, {Laura L.} and Ying Gao and Yuanyuan Fu and Cui Liu and Xiaoyun Chen and Peiqing Liu and Andreas Vogt and Xiao-Ming Yin",
year = "2015",
month = "4",
day = "20",
doi = "10.1371/journal.pone.0122083",
language = "English",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - AMDE-1 is a dual function chemical for autophagy activation and inhibition

AU - Li, Min

AU - Yang, Zuolong

AU - Vollmer, Laura L.

AU - Gao, Ying

AU - Fu, Yuanyuan

AU - Liu, Cui

AU - Chen, Xiaoyun

AU - Liu, Peiqing

AU - Vogt, Andreas

AU - Yin, Xiao-Ming

PY - 2015/4/20

Y1 - 2015/4/20

N2 - Autophagy is the process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy plays important roles in cellular homeostasis and disease pathogenesis. Small chemical molecules that can modulate autophagy activity may have pharmacological value for treating diseases. Using a GFP-LC3-based high content screening assay we identified a novel chemical that is able to modulate autophagy at both initiation and degradation levels. This molecule, termed as Autophagy Modulator with Dual Effect-1 (AMDE-1), triggered autophagy in an Atg5-dependent manner, recruiting Atg16 to the pre-autophagosomal site and causing LC3 lipidation. AMDE-1 induced autophagy through the activation of AMPK, which inactivated mTORC1 and activated ULK1. AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction. Surprisingly, treatment with AMDE-1 resulted in impairment in autophagic flux and inhibition of long-lived protein degradation. This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion. Further analysis indicated that AMDE-1 caused a reduction in lysosome acidity and lysosomal proteolytic activity, suggesting that it suppressed general lysosome function. AMDE-1 thus also impaired endocytosis-mediated EGF receptor degradation. The dual effects of AMDE-1 on autophagy induction and lysosomal degradation suggested that its net effect would likely lead to autophagic stress and lysosome dysfunction, and therefore cell death. Indeed, AMDE-1 triggered necroptosis and was preferentially cytotoxic to cancer cells. In conclusion, this study identified a new class of autophagy modulators with dual effects, which can be explored for potential uses in cancer therapy.

AB - Autophagy is the process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy plays important roles in cellular homeostasis and disease pathogenesis. Small chemical molecules that can modulate autophagy activity may have pharmacological value for treating diseases. Using a GFP-LC3-based high content screening assay we identified a novel chemical that is able to modulate autophagy at both initiation and degradation levels. This molecule, termed as Autophagy Modulator with Dual Effect-1 (AMDE-1), triggered autophagy in an Atg5-dependent manner, recruiting Atg16 to the pre-autophagosomal site and causing LC3 lipidation. AMDE-1 induced autophagy through the activation of AMPK, which inactivated mTORC1 and activated ULK1. AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction. Surprisingly, treatment with AMDE-1 resulted in impairment in autophagic flux and inhibition of long-lived protein degradation. This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion. Further analysis indicated that AMDE-1 caused a reduction in lysosome acidity and lysosomal proteolytic activity, suggesting that it suppressed general lysosome function. AMDE-1 thus also impaired endocytosis-mediated EGF receptor degradation. The dual effects of AMDE-1 on autophagy induction and lysosomal degradation suggested that its net effect would likely lead to autophagic stress and lysosome dysfunction, and therefore cell death. Indeed, AMDE-1 triggered necroptosis and was preferentially cytotoxic to cancer cells. In conclusion, this study identified a new class of autophagy modulators with dual effects, which can be explored for potential uses in cancer therapy.

UR - http://www.scopus.com/inward/record.url?scp=84928571119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928571119&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0122083

DO - 10.1371/journal.pone.0122083

M3 - Article

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e0122083

ER -