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

Fan Zhang, Masafumi Kumano, Eliana Beraldi, Ladan Fazli, Caigan Du, Susan Moore, Poul Sorensen, Amina Zoubeidi and Martin E. Gleave ()
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Fan Zhang: University of British Columbia
Masafumi Kumano: University of British Columbia
Eliana Beraldi: University of British Columbia
Ladan Fazli: University of British Columbia
Caigan Du: University of British Columbia
Susan Moore: University of British Columbia
Poul Sorensen: University of British Columbia
Amina Zoubeidi: University of British Columbia
Martin E. Gleave: University of British Columbia

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6775

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