title: Expression of peroxiredoxins I and IV in multiple myeloma: association with immunoglobulin accumulation.
abstract: B cell malignancies are classified according to the postulated differentiation stage of the originating cell. During differentiation, structural and molecular changes occur to support massive processing of immunoglobulin in the endoplasmic reticulum (ER) of plasma cells at the final stage. When overloaded, the ER generates unfolded proteins and hydrogen peroxide (H2O2), which may cause cell death. Peroxiredoxins (Prxs) I and IV belong to a family of proteins able to catalyze peroxide detoxification. Here, we investigated a potential association of these enzymes with immunoglobulin production in B cell neoplasms. Our results demonstrated that the expression of Prx IV was induced as cells became competent to synthesize immunoglobulin light chains, as observed by immunohistochemistry in tissue sections of B cell neoplasms and also by qPCR and Western blotting analyses in malignant B cell lines. Prx I was frequently highly expressed, indicating additional regulatory processes besides ER activity. Results obtained exclusively with myeloma cells have shown that expression of Prxs I and IV, both at mRNA and protein levels, was associated with light chain secretion quantified by ELISA. We suggest that Prxs I and IV may provide survival advantages for terminally differentiated neoplastic B cells by the elimination of H2O2 and, in the case of Prx IV, by the conversion of this toxic in a functional agent driving oxidative protein folding in the ER. In this sense, multiple myeloma and lymphomas demonstrated to synthesize immunoglobulin chains may benefit from strategic therapies targeting the adaptive pathway to ER stress, including inhibition of Prxs I and IV activity.
authors.affiliation: Faculty of Dentistry, Department of Pathology, São Leopoldo Mandic Institute and Research Center, Rua José Rocha Junqueira, 13, 13045-755 Campinas, São Paulo, Brazil. demasiap@gmail.com
authors.forename: Ana Paula Dias
authors.initials: AP
authors.lastname: Demasi
authors.forename: Elizabeth Ferreira
authors.initials: EF
authors.lastname: Martinez
authors.forename: Marcelo Henrique
authors.initials: MH
authors.lastname: Napimoga
authors.forename: Leandro Lopes
authors.initials: LL
authors.lastname: Freitas
authors.forename: Jose
authors.initials: J
authors.lastname: Vassallo
authors.forename: Adriana Silva Santos
authors.initials: AS
authors.lastname: Duarte
authors.forename: Andresa Borges
authors.initials: AB
authors.lastname: Soares
authors.forename: Ney Soares
authors.initials: NS
authors.lastname: Araujo
authors.forename: Vera Cavalcanti
authors.initials: VC
authors.lastname: Araujo
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007136:Immunoglobulins / Q000096:biosynthesis*; D007150:Immunohistochemistry; D009101:Multiple Myeloma / Q000201:enzymology* / Q000276:immunology; D054464:Peroxiredoxins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D006861:Hydrogen Peroxide; C515940:PRDX1 protein, human; C515980:PRDX4 protein, human; D054464:Peroxiredoxins