title: XIAP and cIAP1 amplifications induce Beclin 1-dependent autophagy through NFκB activation.
abstract: Perturbations in autophagy and apoptosis are associated with cancer development. XIAP and cIAP1 are two members of the inhibitors of apoptosis protein family whose expression is elevated in different cancers. Here we report that XIAP and cIAP1 induce autophagy by upregulating the transcription of Beclin 1, an essential autophagy gene. The E3 ubiquitin ligase activity of both proteins activates NFκB signalling, leading to the direct binding of p65 to the promoter of Beclin 1 and to its transcriptional activation. This mechanism may be relevant in cancer cells, since we found increased levels of autophagy in different B-cell lymphoma-derived cell lines where XIAP is overexpressed and pharmacological inhibition of XIAP in these cell lines reduced autophagosome biogenesis. Thus, the chemotherapy resistance associated with XIAP and cIAP1 overexpression observed in several human cancers may be, at least in part, due to the Beclin 1-dependent autophagy activation by IAPs described in this study. In this context, the disruption of this increased autophagy might represent a valuable pharmacological tool to be included in combined anti-neoplastic therapies.
authors: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors: Fang
authors: F
authors: Lin
authors: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors: Ghita
authors: G
authors: Ghislat
authors: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors: Shouqing
authors: S
authors: Luo
authors: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors: Maurizio
authors: M
authors: Renna
authors: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors: Farah
authors: F
authors: Siddiqi
authors: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK dcr1000@cam.ac.uk.
authors: David C
authors: DC
authors: Rubinsztein
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases