Abstract
In this study, we demonstrated that YM155, a novel survivin suppressant, induced both apoptosis, and autophagy that was shown by conversion of cytosolic-associated protein light chain 3 (LC3I) into autophagosome-associated form (LC3II) and a punctate fluorescence pattern of an ectopic GFP-LC3 protein. The lysosomal inhibitor chloroquine further accumulated YM155-induced LC3II, indicating an increase of autophagic flux. Ectopic expression of survivin significantly attenuated YM155-induced apoptosis and autophagy, whereas survivin siRNA induced autophagy. Furthermore, inhibition of either early or late events of autophagy attenuated YM155-induced apoptosis, demonstrating that induction of autophagy proceeds apoptosis. In conclusion, suppression of survivin by YM155 induces autophagy-dependent apoptosis, and YM155-induced autophagy plays a pro-apoptotic role thereby unveiling a novel mechanism of YM155 in prostate cancer cells.
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Autophagy / drug effects*
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Autophagy / genetics
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Autophagy-Related Protein 5
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Beclin-1
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Blotting, Western
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Cell Line, Tumor
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Chloroquine / pharmacology
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Flow Cytometry
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Imidazoles / pharmacology*
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Inhibitor of Apoptosis Proteins
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Lysosomal Membrane Proteins / genetics
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Lysosomal Membrane Proteins / metabolism
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Lysosomal-Associated Membrane Protein 2
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Microscopy, Confocal
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Microtubule-Associated Proteins / antagonists & inhibitors*
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Naphthoquinones / pharmacology*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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RNA Interference
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Survivin
Substances
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ATG5 protein, human
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Apoptosis Regulatory Proteins
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Autophagy-Related Protein 5
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BECN1 protein, human
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BIRC5 protein, human
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Beclin-1
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Imidazoles
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Inhibitor of Apoptosis Proteins
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LAMP2 protein, human
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Lysosomal-Associated Membrane Protein 2
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Lysosomal Membrane Proteins
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MAP1LC3A protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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Naphthoquinones
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Survivin
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Green Fluorescent Proteins
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Chloroquine
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sepantronium