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

Li M, Yang Z, Vollmer LL, Gao Y, Fu Y, Liu C, Chen X, Liu P, Vogt A, Yin XM - PLoS ONE (2015)

Bottom Line: AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction.This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

A proposed mode for the action of AMDE-1.AMDE-1 can trigger autophagy by the AMPK-mTOR-ULK1 pathway. However, AMDE-1 can also suppress lysosomal function and thus autophagic flux. Consequently, the lysosome dysfunction and/or the accumulation of non-degraded cellular material can promote cell death. The dashed arrow suggests that AMDE-1 may also affect autophagy by other unknown mechanisms.
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pone.0122083.g006: A proposed mode for the action of AMDE-1.AMDE-1 can trigger autophagy by the AMPK-mTOR-ULK1 pathway. However, AMDE-1 can also suppress lysosomal function and thus autophagic flux. Consequently, the lysosome dysfunction and/or the accumulation of non-degraded cellular material can promote cell death. The dashed arrow suggests that AMDE-1 may also affect autophagy by other unknown mechanisms.

Mentions: AMDE-1 is a unique autophagy modulator that emanated from a high throughput screen of 196,160 compounds for LC3-GFP accumulation in punctate structures. Chemicals can affect GFL-LC3 distribution in a number of ways. After excluding non-specific effects, the increase or decrease in GFP-LC3 puncta could be attributed to either changes in autophagy activation or changes in autophagic degradation. Thus positives from the screen could be either autophagy inducers or inhibitors. Using a series of detailed mechanistic studies, we found that AMDE-1 represents a mechanistically unique compound that can exert both effects, but at different stages. Acting as an autophagy activator at the initiation stage and an autophagy inhibitor at the degradation stage causes a significant increase in GFP-LC3 puncta due to the failure to degrade the accumulated autophagosomes (Fig 6).


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

Li M, Yang Z, Vollmer LL, Gao Y, Fu Y, Liu C, Chen X, Liu P, Vogt A, Yin XM - PLoS ONE (2015)

A proposed mode for the action of AMDE-1.AMDE-1 can trigger autophagy by the AMPK-mTOR-ULK1 pathway. However, AMDE-1 can also suppress lysosomal function and thus autophagic flux. Consequently, the lysosome dysfunction and/or the accumulation of non-degraded cellular material can promote cell death. The dashed arrow suggests that AMDE-1 may also affect autophagy by other unknown mechanisms.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403922&req=5

pone.0122083.g006: A proposed mode for the action of AMDE-1.AMDE-1 can trigger autophagy by the AMPK-mTOR-ULK1 pathway. However, AMDE-1 can also suppress lysosomal function and thus autophagic flux. Consequently, the lysosome dysfunction and/or the accumulation of non-degraded cellular material can promote cell death. The dashed arrow suggests that AMDE-1 may also affect autophagy by other unknown mechanisms.
Mentions: AMDE-1 is a unique autophagy modulator that emanated from a high throughput screen of 196,160 compounds for LC3-GFP accumulation in punctate structures. Chemicals can affect GFL-LC3 distribution in a number of ways. After excluding non-specific effects, the increase or decrease in GFP-LC3 puncta could be attributed to either changes in autophagy activation or changes in autophagic degradation. Thus positives from the screen could be either autophagy inducers or inhibitors. Using a series of detailed mechanistic studies, we found that AMDE-1 represents a mechanistically unique compound that can exert both effects, but at different stages. Acting as an autophagy activator at the initiation stage and an autophagy inhibitor at the degradation stage causes a significant increase in GFP-LC3 puncta due to the failure to degrade the accumulated autophagosomes (Fig 6).

Bottom Line: AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction.This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus