Τίτλος:
Sorafenib-induced defective autophagy promotes cell death by necroptosis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencing ULK1 and Beclin1 rescues DU145 cells from cell death indicating that, in this setting, autophagy promotes cell death. Re-expression of Atg5 restores the lipidation of LC3 and rescues DU145 and MEF atg5-/- cells from sorafenib-induced cell death. Despite the lack of Atg5 expression and LC3 lipidation, DU145 cells form autophagosomes as demonstrated by transmission and immuno-electron microscopy, and the formation of LC3 positive foci. However, the lack of cellular content in the autophagosomes, the accumulation of long-lived proteins, the presence of GFP-RFP-LC3 positive foci and the accumulated p62 protein levels indicate that these autophagosomes may not be fully functional. DU145 cells treated with sorafenib undergo a caspase-independent cell death that is inhibited by the RIPK1 inhibitor, necrostatin-1. Furthermore, treatment with sorafenib induces the interaction of RIPK1 with p62, as demonstrated by immunoprecipitation and a proximity ligation assay. Silencing of p62 decreases the RIPK1 protein levels and renders necrostatin-1 ineffective in blocking sorafenib-induced cell death. In summary, the formation of Atg5-deficient autophagosomes in response to sorafenib promotes the interaction of p62 with RIPK leading to cell death by necroptosis.
Συγγραφείς:
Kharaziha, P.
Chioureas, D.
Baltatzis, G.
Fonseca, P.
Rodriguez, P.
Gogvadze, V.
Lennartsson, L.
Björklund, A.-C.
Zhivotovsky, B.
Grandér, D.
Egevad, L.
Nilsson, S.
Panaretakis, T.
Περιοδικό:
OncoTargets and therapy
Εκδότης:
Impact Journals, LLC
Λέξεις-κλειδιά:
autophagy protein 5; beclin 1; caspase; green fluorescent protein; protein kinase; protein p62; receptor interacting protein kinase 1; red fluorescent protein; sorafenib; ULK1 protein; unclassified drug; antineoplastic agent; ATG5 protein, human; Atg5 protein, mouse; autophagy related protein 5; carbanilamide derivative; microtubule associated protein; nicotinamide; P62 protein, human; receptor interacting protein serine threonine kinase; RIPK1 protein, human; RNA binding protein; sorafenib, antineoplastic activity; Article; autophagosome; autophagy; bioaccumulation; cell death; controlled study; drug cytotoxicity; gene silencing; human; human cell; immunoelectron microscopy; immunoprecipitation; light chain; male; prostate cancer cell line; protein protein interaction; transmission electron microscopy; analogs and derivatives; animal; apoptosis; cell culture; drug effects; drug resistance; enzyme immunoassay; fibroblast; flow cytometry; knockout mouse; mammalian embryo; metabolism; mouse; necrosis; pathology; phagosome; physiology; Prostatic Neoplasms; tissue microarray; Western blotting, Animals; Antineoplastic Agents; Apoptosis; Autophagy; Autophagy-Related Protein 5; Blotting, Western; Cells, Cultured; Drug Resistance, Neoplasm; Embryo, Mammalian; Fibroblasts; Flow Cytometry; Humans; Immunoenzyme Techniques; Immunoprecipitation; Male; Mice; Mice, Knockout; Microtubule-Associated Proteins; Necrosis; Niacinamide; Phagosomes; Phenylurea Compounds; Prostatic Neoplasms; Receptor-Interacting Protein Serine-Threonine Kinases; RNA-Binding Proteins; Tissue Array Analysis
DOI:
10.18632/oncotarget.5797
