Abstract
We recently isolated a macrocyclic compound, versipelostatin (VST), that exerts in vivo antitumor activity. VST shows unique, selective cytotoxicity to glucose-deprived tumor cells by preventing the unfolded protein response (UPR). Here we show that eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of eukaryotic initiation factor 4E-mediated protein translation, plays a role in the UPR-inhibitory action of VST. Indeed, 4E-BP1 is aberrantly activated by VST. This activation occurs specifically during glucose deprivation and results in profound translation repression and prevents induction of the typical UPR markers glucose-regulated protein (GRP) 78 and activating transcription factor (ATF) 4. Our overexpression and knockdown experiments showed that 4E-BP1 can regulate GRP78 and ATF4 expression. These mechanisms appear to be specific for VST. By contrast, rapamycin, which activates 4E-BP1 regardless of cellular glucose availability, has only marginal effects on the expression of GRP78 and ATF4. Our present findings demonstrate that aberrant 4E-BP1 activation can contribute to UPR preventing by VST, possibly through a mechanism that does not operate in rapamycin-treated cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 4 / genetics
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Activating Transcription Factor 4 / metabolism*
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Apoptosis / drug effects
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Blotting, Western
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Cell Cycle Proteins
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Cell Proliferation / drug effects
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Cells, Cultured
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Endoplasmic Reticulum Chaperone BiP
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Gene Expression Regulation / drug effects*
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Humans
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Immunosuppressive Agents / pharmacology
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Luciferases / metabolism
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Macrolides / pharmacology*
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Oligosaccharides / pharmacology*
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation / drug effects
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Protein Biosynthesis / drug effects
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RNA, Small Interfering / genetics
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Sirolimus / pharmacology
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Unfolded Protein Response / drug effects*
Substances
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ATF4 protein, human
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Endoplasmic Reticulum Chaperone BiP
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HSPA5 protein, human
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Heat-Shock Proteins
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Immunosuppressive Agents
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Macrolides
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Oligosaccharides
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Phosphoproteins
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RNA, Small Interfering
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versipelostatin
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Activating Transcription Factor 4
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Luciferases
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Sirolimus