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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Zuolong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: University of Pittsburgh Drug Discovery Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Vollmer
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
authors.affiliation: University of Pittsburgh Drug Discovery Institute, Pittsburgh, Pennsylvania, United States of America; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071189:Autophagy-Related Protein-1 Homolog; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D000071187:Autophagy-Related Protein 5; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D000071189:Autophagy-Related Protein-1 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; D055372:AMP-Activated Protein Kinases