title: The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells.
abstract: HSP60 undergoes changes in quantity and distribution in some types of tumors suggesting a participation of the chaperonin in the mechanism of transformation and cancer progression. Suberoylanilide hydroxamic acid (SAHA), a member of a family of histone deacetylase inhibitors (HDACi), has anti-cancer potential but its interaction, if any, with HSP60 has not been elucidated. We investigated the effects of SAHA in a human lung-derived carcinoma cell line (H292). We analysed cell viability and cycle; oxidative stress markers; mitochondrial integrity; HSP60 protein and mRNA levels; and HSP60 post-translational modifications, and its secretion. We found that SAHA is cytotoxic for H292 cells, interrupting the cycle at the G2/M phase, which is followed by death; cytotoxicity is associated with oxidative stress, mitochondrial damage, and diminution of intracellular levels of HSP60; HSP60 undergoes a post-translational modification and becomes nitrated; and nitrated HSP60 is exported via exosomes. We propose that SAHA causes ROS overproduction and mitochondrial dysfunction, which leads to HSP60 nitration and release into the intercellular space and circulation to interact with the immune system. These successive steps might constitute the mechanism of the anti-tumor action of SAHA and provide a basis to design supplementary therapeutic strategies targeting HSP60, which would be more efficacious than the compound alone.
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.|Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Campanella
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Palermo, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Anneo
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.|Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Marino Gammazza
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.|Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Celeste
authors.initials: C
authors.lastname: Caruso Bavisotto
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.|Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Barone
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo, Palermo, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Emanuele
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.
authors.forename: Filippa
authors.initials: F
authors.lastname: Lo Cascio
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Mocciaro
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, National Institute of Health (ISS), Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore and IMET, Columbus Center, Baltimore, USA.
authors.forename: Everly
authors.initials: E
authors.lastname: Conway De Macario
authors.affiliation: Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.|Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore and IMET, Columbus Center, Baltimore, USA.
authors.forename: Alberto J L
authors.initials: AJ
authors.lastname: Macario
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.|Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cappello
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo, Palermo, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Lauricella
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018834:Chaperonin 60 / Q000187:drug effects* / Q000378:metabolism*; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000187:drug effects* / Q000378:metabolism*; D015538:Nitrosation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D018834:Chaperonin 60; C060293:HSPD1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D024101:Mitochondrial Proteins; D000077337:Vorinostat
keywords: HSP60; SAHA; exosomes; histone deacetylase inhibitor; oxidative stress