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

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

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Autophagy / drug effects
  • Autophagy / genetics
  • Autophagy-Related Proteins
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Clusterin / antagonists & inhibitors
  • Clusterin / deficiency
  • Clusterin / genetics*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lipid Metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Phagosomes / drug effects
  • Phagosomes / metabolism*
  • Phagosomes / pathology
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Signal Transduction
  • Thionucleotides / genetics
  • Thionucleotides / metabolism
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Autophagy-Related Proteins
  • CLU protein, human
  • Clusterin
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • OGX-011
  • Pyrimidines
  • Pyrroles
  • Thionucleotides
  • Ubiquitin-Conjugating Enzymes
  • ATG3 protein, human
  • capivasertib