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

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.
Mesh Terms:
Animals, Apoptosis, Autophagy, Cell Line, Tumor, Cell Survival, Clusterin, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Lipid Metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Microtubule-Associated Proteins, Phagosomes, Prostatic Neoplasms, Pyrimidines, Pyrroles, Signal Transduction, Thionucleotides, Ubiquitin-Conjugating Enzymes, Xenograft Model Antitumor Assays
Nat Commun
Date: Dec. 17, 2014
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