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BH3 mimetics activate multiple pro-autophagic pathways

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-XL, 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.

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Acknowledgements

We thank Drs B Vogelstein (John Hopkins University, Bethesda, MD, USA) and S Korsmeyer (Harvard University) for HCT116 cells and double-knockout MEF, respectively. We thank Dr K-L Guan for Rheb constructs. GK is supported by the Ligue Nationale contre le Cancer (Equipes labellisée), Agence Nationale pour la Recherche (ANR), AXA Foundation (Chair for Longevity Research), European Commission (Active p53, Apo-Sys, ChemoRes, ApopTrain, ArtForce), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa) and Cancéropôle Ile-de-France. SA Malik is the recipient of a grant from the Higher Education Commission (HEC) of Pakistan.

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Correspondence to G Kroemer.

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Malik, S., Orhon, I., Morselli, E. et al. BH3 mimetics activate multiple pro-autophagic pathways. Oncogene 30, 3918–3929 (2011). https://doi.org/10.1038/onc.2011.104

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