Abstract
The BH3 mimetic ABT737 induces autophagy by competitively disrupting the inhibitory interaction between the BH3 domain of Beclin 1 and the anti-apoptotic proteins Bcl-2 and Bcl-X(L), thereby stimulating the Beclin 1-dependent allosteric activation of the pro-autophagic lipid kinase VPS34. Here, we examined whether ABT737 stimulates other pro-autophagic signal-transduction pathways. ABT737 caused the activating phosphorylation of AMP-dependent kinase (AMPK) and of the AMPK substrate acetyl CoA carboxylase, the activating phosphorylation of several subunits of the inhibitor of NF-κB (IκB) kinase (IKK) and the hyperphosphorylation of the IKK substrate IκB, inhibition of the activity of mammalian target of rapamycin (mTOR) and consequent dephosphorylation of the mTOR substrate S6 kinase. In addition, ABT737 treatment dephosphorylates (and hence likewise inhibits) p53, glycogen synthase kinase-3 and Akt. All these effects were shared by ABT737 and another structurally unrelated BH3 mimetic, HA14-1. Functional experiments revealed that pharmacological or genetic inhibition of IKK, Sirtuin and the p53-depleting ubiquitin ligase MDM2 prevented ABT737-induced autophagy. These results point to unexpected and pleiotropic pro-autophagic effects of BH3 mimetics involving the modulation of multiple signalling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetyl-CoA Carboxylase / metabolism
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Apoptosis Regulatory Proteins / agonists*
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Autophagy / drug effects*
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Beclin-1
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Benzopyrans / pharmacology
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Biphenyl Compounds / pharmacology*
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Cell Line, Tumor
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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I-kappa B Kinase / metabolism
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Membrane Proteins / agonists*
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Nitriles / pharmacology
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Nitrophenols / pharmacology*
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Oncogene Protein v-akt / metabolism
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Phosphorylation
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Phosphotransferases (Phosphate Group Acceptor) / metabolism
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Ribosomal Protein S6 Kinases / metabolism
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Signal Transduction / drug effects
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Sirtuins / metabolism
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Sulfonamides / pharmacology*
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TOR Serine-Threonine Kinases / metabolism
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Tumor Suppressor Protein p53 / metabolism
Substances
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ABT-737
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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Benzopyrans
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Biphenyl Compounds
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Membrane Proteins
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Nitriles
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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Tumor Suppressor Protein p53
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ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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MTOR protein, human
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Oncogene Protein v-akt
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Ribosomal Protein S6 Kinases
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TOR Serine-Threonine Kinases
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I-kappa B Kinase
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Glycogen Synthase Kinase 3
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AMP-dependent kinase (ATP-forming)
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Phosphotransferases (Phosphate Group Acceptor)
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Sirtuins
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Acetyl-CoA Carboxylase