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XIAP and cIAP1 amplifications induce Beclin 1-dependent autophagy through NFκB activation.


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Authors

Lin, Fang 
Ghislat, Ghita 
Luo, Shouqing 
Renna, Maurizio 

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.

Description

Keywords

Apoptosis Regulatory Proteins, Autophagy, Beclin-1, Humans, Inhibitor of Apoptosis Proteins, Membrane Proteins, NF-kappa B, Signal Transduction, Transcriptional Activation, Ubiquitin-Protein Ligases, X-Linked Inhibitor of Apoptosis Protein

Journal Title

Hum Mol Genet

Conference Name

Journal ISSN

0964-6906
1460-2083

Volume Title

24

Publisher

Oxford University Press (OUP)
Sponsorship
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (095317/Z/11/A)
European Commission (264508)
We are grateful for funding from the Wellcome Trust (Principal Fellowship to D.C.R), NIHR Biomedical Research Unit in Dementia at Addenbrooke's Hospital, the Treat PolyQ project (European community's Seventh Framework Programme under grant agreement no. 264508), and the Jiangsu Government Scholarship for Overseas Studies. Funding to pay the Open Access publication charges for this article was provided by Wellcome Trust.