title: Tissue transglutaminase (TG2) is involved in the resistance of cancer cells to the histone deacetylase (HDAC) inhibitor vorinostat.
abstract: Vorinostat demonstrated preclinical and clinical efficacy in human cancers and is the first histone deacetylase inhibitor (HDACi) approved for cancer treatment. Tissue transglutaminase (TG2) is a multifunctional enzyme that catalyzes a Ca2+dependent transamidating reaction resulting in covalent cross-links between proteins. TG2 acts also as G-protein in trans-membrane signaling and as a cell surface adhesion mediator. TG2 up-regulation has been demonstrated in several cancers and its expression levels correlate with resistance to chemotherapy and metastatic potential. We demonstrated that the anti-proliferative effect of the HDACi vorinostat is paralleled by the induction of TG2 mRNA and protein expression in cancer cells but not in ex vivo treated peripheral blood lymphocytes. This effect was also shared by other pan-HDACi and resulted in increased TG2 transamidating activity. Notably, high TG2 basal levels in a panel of cancer cell lines correlated with lower vorinostat antiproliferative activity. Notably, in TG2-knockdown cancer cells vorinostat anti-proliferative and pro-apoptotic effects were enhanced, whereas in TG2-full-length transfected cells were impaired, suggesting that TG2 could represent a mechanism of intrinsic or acquired resistance to vorinostat. In fact, co-treatment of tumor cells with inhibitors of TG2 transamidating activity potentiated the antitumor effect of vorinostat. Moreover, vorinostat-resistant MCF7 cells selected by stepwise increasing concentrations of the drug, significantly overexpressed TG2 protein compared to parental cells, and co-treatment of these cells with TG2 inhibitors reversed vorinostat-resistance. Taken together, our data demonstrated that TG2 is involved in the resistance of cancer cells to vorinostat, as well as to other HDACi.
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131, Naples, Italy.|Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Carbone
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131, Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Di Gennaro
authors.affiliation: Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy.|Laboratory of Oncology and Molecular Therapy, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Geny
authors.initials: G
authors.lastname: Piro
authors.affiliation: Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Milone
authors.affiliation: Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: Pucci
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131, Naples, Italy. a.budillon@istitutotumori.na.it.|Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy. a.budillon@istitutotumori.na.it.
authors.forename: Alfredo
authors.identifier: 0000-0001-6631-3550
authors.initials: A
authors.lastname: Budillon
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D061986:MCF-7 Cells; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007555:Isoxazoles; C510621:KCC 009; D034741:RNA, Small Interfering; D000077337:Vorinostat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D006655:Histone Deacetylases; D019204:GTP-Binding Proteins
keywords: Cancer; Histone deacetylase inhibitors; Transglutaminase-2; Vorinostat