title: Potassium Bisperoxo(1,10-phenanthroline)oxovanadate (bpV(phen)) Induces Apoptosis and Pyroptosis and Disrupts the P62-HDAC6 Protein Interaction to Suppress the Acetylated Microtubule-dependent Degradation of Autophagosomes.
abstract: Autophagy is a cellular process that controls and executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activates the initiation of autophagy. Autophagosomes migrate along acetylated microtubules to fuse with lysosomes to execute the degradation of the engulfed substrates that usually bind with sequestosome 1 (SQSTM1, p62). Microtubule-associated protein 1 light chain 3 (LC3) traces the autophagy process by converting from the LC3-I to the LC3-II isoform and serves as a major marker of autophagy flux. Potassium bisperoxo(1,10-phenanthroline)oxovanadate (bpV(phen)) is an insulin mimic and a PTEN inhibitor and has the potential to treat different diseases. Here we show that bpV(phen) enhances the ubiquitination of p62, reduces the stability of p62, disrupts the interaction between p62 and histone deacetylase 6 (HDAC6), activates the deacetylase activity of HDAC6 on α-tubulin, and impairs stable acetylated microtubules. Microtubular destabilization leads to the blockade of autophagosome-lysosome fusion and accumulation of autophagosomes. Autophagy defects lead to oxidative stress and lysosomal rupture, which trigger different types of cell death, including apoptosis and pyroptosis. The consistent results from multiple systems, including mouse and different types of mammalian cells, are different from the predicted function of bpV(phen) as a PTEN inhibitor to activate autophagy flux. In addition, levels of p62 are reduced but not elevated when autophagosomal degradation is blocked, revealing a novel function of p62 in autophagy regulation. Therefore, it is necessary to pay attention to the roles of bpV(phen) in autophagy, apoptosis, and pyroptosis when it is developed as a drug.
authors.affiliation: From the School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province 230032, China, the Department of Anesthesiology, Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui Province, 230601, China, the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Fei
authors.initials: F
authors.lastname: Yue
authors.affiliation: the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Li
authors.affiliation: the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.affiliation: From the School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province 230032, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: From the School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: the Department of Anesthesiology, Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui Province, 230601, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Kun
authors.initials: K
authors.lastname: Song
authors.affiliation: the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Guanqun
authors.initials: G
authors.lastname: Huang
authors.affiliation: the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Guibin
authors.initials: G
authors.lastname: Xu
authors.affiliation: the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: From the School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province 230032, China, lj@ahmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and the Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, Texas 77843 lliu@ibt.tamhsc.edu.
authors.forename: Leyuan
authors.initials: L
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D015388:Organelles / Q000187:drug effects* / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010618:Phenanthrolines / Q000494:pharmacology*; D011485:Protein Binding; D000069292:Pyroptosis / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D009942:Organometallic Compounds; C118585:P62 protein, human; D010618:Phenanthrolines; D016601:RNA-Binding Proteins; D014404:Tubulin; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: apoptosis; autophagy; bpV(phen); caspase 1 (CASP1); histone deacetylase 6 (HDAC6); lactate dehydrogenase; microtubule; p62 (sequestosome 1(SQSTM1)); pyroptosis; tubulin