title: 4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas.
abstract: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is over-expressed in several human neoplastic cells. When MIF binds its receptor (CD74) and co-receptor (CD44), it initiates signaling cascades that orchestrate cell proliferation and survival, and it can directly modulate the activity of AMPK. These activities indicate that MIF potentially regulates cell survival and metabolism. We found that MIF was primarily co-expressed with CD74 in 16 out of 23 papillary thyroid carcinoma (PTC) and in all the 27 available anaplastic thyroid carcinoma (ATC) biopsy samples. MIF and CD74 were co-expressed in TPC-1 and HTC-C3 cell lines. The selective MIF inhibitor, 4-iodo-6-phenylpyrimidine (4-IPP), blocked MIF/CD74 internalization, activated JNK, and dose-dependently inhibited proliferation inducing apoptosis and mitotic cell death. In two CD74-negative cell lines, NIM-1 and K1, 4-IPP treatment partially reduced proliferation. Coordinated MIF and CD74 expression appeared to confer in tumor cells the plasticity necessary to escape cell cycle regulation, metabolic changes, and stress conditions. MIF/CD74 signaling removal made cells susceptible to apoptosis and mitotic cell death. This finding suggests a possible avenue for targeting DNA endoreduplication, thus preventing the proliferation of therapy-resistant cell subpopulations. This study highlights MIF/CD74 axis as an important player in the biology of aggressive thyroid neoplasms.
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Varinelli
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Caccia
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Chiara C
authors.initials: CC
authors.lastname: Volpi
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Caccia
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Maida
authors.initials: M
authors.lastname: De Bortoli
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Taverna
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Ambra V
authors.initials: AV
authors.lastname: Gualeni
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Annunziata
authors.initials: A
authors.lastname: Gloghini
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Manenti
authors.affiliation: Proteomics LaboratoryDepartment of Experimental Oncology and Molecular MedicineDepartment of Diagnostic Pathology and Laboratory MedicineDepartment of Predictive and Preventive MedicineFondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyLaboratory of Clinical Pathology and Medical GeneticsFondazione IRCCS 'Carlo Besta' Istituto Neurologico, Via Amadeo 42, 20133 Milan, Italy italia.bongarzone@istitutotumori.mi.it.
authors.forename: Italia
authors.initials: I
authors.lastname: Bongarzone
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002291:Carcinoma, Papillary; D002453:Cell Cycle; D049109:Cell Proliferation; D002853:Chromatography, Liquid / Q000379:methods; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055442:Metabolome; D008938:Mitosis / Q000187:drug effects*; D020543:Proteome / Q000032:analysis*; D011971:Receptors, Immunologic / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000379:methods; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; D008263:Macrophage Migration-Inhibitory Factors; D020543:Proteome; D011971:Receptors, Immunologic; C033184:macrophage migration inhibitory factor receptor; C041272:indolepropanol phosphate; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: 4-IPP; AMPK; CD74; anaplastic thyroid carcinoma; endoreduplication; macrophage migration inhibitory factor; papillary thyroid carcinoma