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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References
Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A . (2008). Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res 68: 1485–1494.
Benit P, Goncalves S, Philippe Dassa E, Briere JJ, Martin G, Rustin P . (2006). Three spectrophotometric assays for the measurement of the five respiratory chain complexes in minuscule biological samples. Clin Chim Acta 374: 81–86.
Boya P, González-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N et al. (2005). Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 25: 1025–1040.
Boya P, Kroemer G . (2009). Beclin 1: a BH3-only protein that fails to induce apoptosis. Oncogene 28: 2125–2127.
Broemer M, Krappmann D, Scheidereit C . (2004). Requirement of Hsp90 activity for IkappaB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-kappaB activation. Oncogene 23: 5378–5386.
Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E, Vitale I et al. (2010). The IKK complex contributes to the induction of autophagy. EMBO J 29: 619–631.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G et al. (2006). Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10: 51–64.
Galluzzi L, Maiuri MC, Vitale I, Zischka H, Castedo M, Zitvogel L et al. (2007). Cell death modalities: classification and pathophysiological implications. Cell Death Differ 14: 1237–1243.
Galluzzi L, Vicencio JM, Kepp O, Tasdemir E, Maiuri MC, Kroemer G . (2008). To die or not to die: that is the autophagic question. Curr Mol Med 8: 78–91.
Harborth J, Elbashir SM, Bechert K, Tuschl T, Weber K . (2001). Identification of essential genes in cultured mammalian cells using small interfering RNAs. J Cell Sci 114: 4557–4565.
Huang DC, Strasser A . (2000). BH3-Only proteins-essential initiators of apoptotic cell death. Cell 103: 839–842.
Iwata A, Riley BE, Johnston JA, Kopito RR . (2005). HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 280: 40282–40292.
Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T et al. (2000). LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19: 5720–5728.
Kessel D, Reiners Jr JJ . (2007). Initiation of apoptosis and autophagy by the Bcl-2 antagonist HA14-1. Cancer Lett 249: 294–299.
Klionsky DJ . (2007). Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8: 931–937.
Klionsky DJ, Codogno P, Cuervo AM, Deretic V, Elazar Z, Fueyo-Margareto J et al. (2010). A comprehensive glossary of autophagy-related molecules and processes. Autophagy 6: 438–448.
Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE et al. (2008). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105: 3374–3379.
Levine B, Kroemer G . (2008). Autophagy in the pathogenesis of disease. Cell 132: 27–42.
Lian J, Wu X, He F, Karnak D, Tang W, Meng Y et al. (2010). A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum. Cell Death Differ 18: 60–71.
Madeo F, Tavernarakis N, Kroemer G . (2010). Can autophagy promote longevity? Nat Cell Biol 12: 842–846.
Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA et al. (2007a). BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy 3: 374–376.
Maiuri MC, Galluzzi L, Morselli E, Kepp O, Malik SA, Kroemer G . (2010). Autophagy regulation by p53. Curr Opin Cell Biol 22: 181–185.
Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P et al. (2007b). Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26: 2527–2539.
Maiuri MC, Malik SA, Morselli E, Kepp O, Criollo A, Mouchel PL et al. (2009). Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 8: 1571–1576.
Maiuri MC, Zalckvar E, Kimchi A, Kroemer G . (2007c). Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8: 741–752.
Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S et al. (2007). Programmed anuclear cell death delimits platelet life span. Cell 128: 1173–1186.
Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras K et al. (2010). Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis 1: e10.
Oberstein A, Jeffrey PD, Shi Y . (2007). Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem 282: 13123–13132.
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA et al. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677–681.
Petros AM, Olejniczak ET, Fesik SW . (2004). Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 1644: 83–94.
Pierce JW, Schoenleber R, Jesmok G, Best J, Moore SA, Collins T et al. (1997). Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J Biol Chem 272: 21096–21103.
Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM et al. (1994). Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228: 35–51.
Sinha S, Levine B . (2008). The autophagy effector Beclin 1: a novel BH3-only protein. Oncogene 27: S137–S148.
Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D'Amelio M et al. (2008a). Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10: 676–687.
Tasdemir E, Maiuri MC, Orhon I, Kepp O, Morselli E, Criollo A et al. (2008b). p53 represses autophagy in a cell cycle-dependent fashion. Cell Cycle 7: 3006–3011.
Yang Z, Klionsky DJ . (2010). Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22: 124–131.
Zhang XD, Wang Y, Wu JC, Lin F, Han R, Han F et al. (2009). Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum. J Neurosci Res 87: 3600–3610.
Zhou X, Ikenoue T, Chen X, Li L, Inoki K, Guan KL . (2009). Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. Proc Natl Acad Sci USA 106: 8923–8928.
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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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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DOI: https://doi.org/10.1038/onc.2011.104
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