title: HSPH1 inhibition downregulates Bcl-6 and c-Myc and hampers the growth of human aggressive B-cell non-Hodgkin lymphoma.
abstract: We have shown that human B-cell non-Hodgkin lymphomas (B-NHLs) express heat shock protein (HSP)H1/105 in function of their aggressiveness. Here, we now clarify its role as a functional B-NHL target by testing the hypothesis that it promotes the stabilization of key lymphoma oncoproteins. HSPH1 silencing in 4 models of aggressive B-NHLs was paralleled by Bcl-6 and c-Myc downregulation. In vitro and in vivo analysis of HSPH1-silenced Namalwa cells showed that this effect was associated with a significant growth delay and the loss of tumorigenicity when 10(4) cells were injected into mice. Interestingly, we found that HSPH1 physically interacts with c-Myc and Bcl-6 in both Namalwa cells and primary aggressive B-NHLs. Accordingly, expression of HSPH1 and either c-Myc or Bcl-6 positively correlated in these diseases. Our study indicates that HSPH1 concurrently favors the expression of 2 key lymphoma oncoproteins, thus confirming its candidacy as a valuable therapeutic target of aggressive B-NHLs.
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Zappasodi
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
authors.forename: Giusi
authors.initials: G
authors.lastname: Ruggiero
authors.affiliation: Tumor Immunology Unit, Department of Health Science, Human Pathology Section, School of Medicine, University of Palermo, Palermo, Italy;
authors.forename: Carla
authors.initials: C
authors.lastname: Guarnotta
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy;
authors.forename: Cristina
authors.initials: C
authors.lastname: Tringali
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cavanè
authors.affiliation: Pathology Unit, Department of Medical Oncology, and.
authors.forename: Antonello D
authors.initials: AD
authors.lastname: Cabras
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; and.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Castagnoli
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy;
authors.forename: Bruno
authors.initials: B
authors.lastname: Venerando
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; Medical Oncology, University of Milan, Milan, Italy.
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Gianni
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
authors.forename: Filippo
authors.initials: F
authors.lastname: De Braud
authors.affiliation: Tumor Immunology Unit, Department of Health Science, Human Pathology Section, School of Medicine, University of Palermo, Palermo, Italy;
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; and.
authors.forename: Serenella M
authors.initials: SM
authors.lastname: Pupa
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Nicola
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D050957:HSP110 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D050957:HSP110 Heat-Shock Proteins; C097205:HSPH1 protein, human; C489427:MYC protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc