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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Autophagy / drug effects
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Autophagy / genetics
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Autophagy-Related Proteins
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Cell Line, Tumor
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Cell Survival / drug effects
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Clusterin / antagonists & inhibitors
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Clusterin / deficiency
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Clusterin / genetics*
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic*
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Humans
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Lipid Metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Nude
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Microtubule-Associated Proteins / antagonists & inhibitors
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Microtubule-Associated Proteins / genetics*
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Microtubule-Associated Proteins / metabolism
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Phagosomes / drug effects
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Phagosomes / metabolism*
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Phagosomes / pathology
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Pyrimidines / pharmacology
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Pyrroles / pharmacology
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Signal Transduction
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Thionucleotides / genetics
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Thionucleotides / metabolism
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Ubiquitin-Conjugating Enzymes / genetics
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Ubiquitin-Conjugating Enzymes / metabolism
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Xenograft Model Antitumor Assays
Substances
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Autophagy-Related Proteins
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CLU protein, human
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Clusterin
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MAP1LC3A protein, human
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Microtubule-Associated Proteins
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OGX-011
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Pyrimidines
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Pyrroles
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Thionucleotides
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Ubiquitin-Conjugating Enzymes
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ATG3 protein, human
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capivasertib