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Nat Commun. 2014 Dec 12;5:5775. doi: 10.1038/ncomms6775.

Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival.

Author information

1
1] The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6 [2].
2
The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
3
1] The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6 [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.

Abstract

We define stress-induced adaptive survival pathways linking autophagy with the molecular chaperone clusterin (CLU) that function to promote anticancer treatment resistance. During treatment stress, CLU co-localizes with LC3 via an LIR-binding sequence within autophagosome membranes, functioning to facilitate LC3-Atg3 heterocomplex stability and LC3 lipidation, and thereby enhance autophagosome biogenesis and autophagy activation. Stress-induced autophagy is attenuated with CLU silencing in CLU(-/-) mice and human prostate cancer cells. CLU-enhanced cell survival occurs via autophagy-dependent pathways, and is reduced following autophagy inhibition. Combining CLU inhibition with anticancer treatments attenuates autophagy activation, increases apoptosis and reduces prostate cancer growth. This study defines a novel adaptor protein function for CLU under stress conditions, and highlights how co-targeting CLU and autophagy can amplify proteotoxic stress to delay cancer progression.

PMID:
25503391
PMCID:
PMC4275590
DOI:
10.1038/ncomms6775
[Indexed for MEDLINE]
Free PMC Article

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