title: TRAP1 regulates cell cycle and apoptosis in thyroid carcinoma cells.
abstract: Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a heat shock protein 90 (HSP90) molecular chaperone upregulated in several human malignancies and involved in protection from apoptosis and drug resistance, cell cycle progression, cell metabolism and quality control of specific client proteins. TRAP1 role in thyroid carcinoma (TC), still unaddressed at present, was investigated by analyzing its expression in a cohort of 86 human TCs and evaluating its involvement in cancer cell survival and proliferation in vitro Indeed, TRAP1 levels progressively increased from normal peritumoral thyroid gland, to papillary TCs (PTCs), follicular variants of PTCs (FV-PTCs) and poorly differentiated TCs (PDTCs). By contrast, anaplastic thyroid tumors exhibited a dual pattern, the majority being characterized by high TRAP1 levels, while a small subgroup completely negative. Consistently with a potential involvement of TRAP1 in thyroid carcinogenesis, TRAP1 silencing resulted in increased sensitivity to paclitaxel-induced apoptosis, inhibition of cell cycle progression and attenuation of ERK signaling. Noteworthy, the inhibition of TRAP1 ATPase activity by pharmacological agents resulted in attenuation of cell proliferation, inhibition of ERK signaling and reversion of drug resistance. These data suggest that TRAP1 inhibition may be regarded as potential strategy to target specific features of human TCs, i.e., cell proliferation and resistance to apoptosis.
authors.affiliation: Medical Oncology UnitDepartment of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palladino
authors.affiliation: Laboratory of Pre-Clinical and Translational ResearchIRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Notarangelo
authors.affiliation: Anatomic Pathology UnitDepartment of Clinic and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pannone
authors.affiliation: Medical Oncology UnitDepartment of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Piscazzi
authors.affiliation: Endocrinology UnitDepartment of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Lamacchia
authors.affiliation: Laboratory of Pre-Clinical and Translational ResearchIRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Sisinni
authors.affiliation: Medical Oncology UnitDepartment of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Spagnoletti
authors.affiliation: Pathology UnitDepartment of Human Pathology and Oncology, University of Siena, Siena, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Toti
authors.affiliation: Institute of Histopathology and Diagnostic CytopathologyFondazione di Ricerca e Cura 'Giovanni Paolo II' UCSC, Campobasso, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Nuclear Medicine UnitIRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Storto
authors.affiliation: Anatomic Pathology UnitDepartment of Clinic and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Bufo
authors.affiliation: Endocrinology UnitDepartment of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Cignarelli
authors.affiliation: Department of Molecular Medicine and Medical BiotechnologyUniversity of Naples Federico II, Naples, Italy matteo.landriscina@unifg.it franca.esposito@unina.it.
authors.forename: Franca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Medical Oncology UnitDepartment of Medical and Surgical Sciences, University of Foggia, Foggia, Italy Laboratory of Pre-Clinical and Translational ResearchIRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy matteo.landriscina@unifg.it franca.esposito@unina.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Landriscina
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C570862:2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one; D000970:Antineoplastic Agents; D006146:Guanidines; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011728:Pyridones; D011743:Pyrimidines; C092306:TRAP1 protein, human; C557898:gamitrinib-G4; D017239:Paclitaxel
keywords: HSP990; TRAP1; apoptosis; cell cycle; thyroid carcinoma