title: Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival.
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.
authors.affiliation: 1] The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6 [2].
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 1] The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6 [2].
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kumano
authors.affiliation: The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: Eliana
authors.initials: E
authors.lastname: Beraldi
authors.affiliation: The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: Caigan
authors.initials: C
authors.lastname: Du
authors.affiliation: The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: Susan
authors.initials: S
authors.lastname: Moore
authors.affiliation: 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.
authors.forename: Poul
authors.initials: P
authors.lastname: Sorensen
authors.affiliation: The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.affiliation: The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071183:Autophagy-Related Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051152:Clusterin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071183:Autophagy-Related Proteins; C495242:CLU protein, human; D051152:Clusterin; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C503781:OGX-011; D011743:Pyrimidines; D011758:Pyrroles; D013873:Thionucleotides; D044763:Ubiquitin-Conjugating Enzymes; C455621:ATG3 protein, human; C575618:capivasertib