title: Poly-ADP-ribosylation of HMGB1 regulates TNFSF10/TRAIL resistance through autophagy.
abstract: Both apoptosis ("self-killing") and autophagy ("self-eating") are evolutionarily conserved processes, and their crosstalk influences anticancer drug sensitivity and cell death. However, the underlying mechanism remains unclear. Here, we demonstrated that HMGB1 (high mobility group box 1), normally a nuclear protein, is a crucial regulator of TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10)-induced cancer cell death. Activation of PARP1 (poly [ADP-ribose] polymerase 1) was required for TNFSF10-induced ADP-ribosylation of HMGB1 in cancer cells. Moreover, pharmacological inhibition of PARP1 activity or knockdown of PARP1 gene expression significantly inhibited TNFSF10-induced HMGB1 cytoplasmic translocation and subsequent HMGB1-BECN1 complex formation. Furthermore, suppression of the PARP1-HMGB1 pathway diminished autophagy, increased apoptosis, and enhanced the anticancer activity of TNFSF10 in vitro and in a subcutaneous tumor model. These results indicate that PARP1 acts as a prominent upstream regulator of HMGB1-mediated autophagy and maintains a homeostatic balance between apoptosis and autophagy, which provides new insight into the mechanism of TNFSF10 resistance.
authors.affiliation: a Department of Pediatrics; Xiangya Hospital ; Central South University ; Changsha , Hunan China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Yang
authors.forename: Liying
authors.initials: L
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.forename: Liangchun
authors.initials: L
authors.lastname: Yang
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D024243:HMGB1 Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: ATG, autophagy-related; DISC, death-inducing signaling complex; HMGB1; HMGB1, high mobility group box 1; MAP1LC3A/LC3, microtubule-associated protein 1 light chain 3 α; PARP-1; PARP1, poly (ADP-ribose) polymerase 1; PARylation, poly-ADP-ribosylation; RIPK1/RIP, receptor (TNFRSF)-interacting serine-threonine kinase 1; TNF, tumor necrosis factor; TNFSF10/TRAIL, tumor necrosis factor (ligand) superfamily, member 10; TRAIL; TUNEL, TdT-mediated dUTP-X nick end labeling; apoptosis; autophagy; shRNA, short hairpin RNA