title: Targeting BAG-1: a novel strategy to increase drug efficacy in acute myeloid leukemia.
abstract: Overexpression of antiapoptotic proteins occurs frequently in cancer, resulting in defective apoptosis that may contribute to a poor chemosensitivity of tumor cells. B-cell lymphoma (BCL) 2-associated AthanoGene-1 (BAG-1) is a prosurvival chaperone recently found involved in the maintenance of acute myeloid leukemia (AML) cells survival in vitro. Here we reported BAG-1 upregulation in 87 of 99 analyzed AML patients with respect to healthy control samples applying reverse phase protein assay. Silencing of BAG-1 expression confirmed a decreased BCL-2 protein level but, in addition, provoked the increased transcription of GADD34 stress sensor. Furthermore, a dephosphorylation of eIF2α, as well as alteration of expression of IRE-1 and CHOP proteins, were documented, suggesting that a disruption of the endoplasmic reticulum stress/unfolded protein response was provoked by downregulation of BAG-1. A similar phenomenon was triggered after addition of Thioflavin S, which was shown to block BAG-1/BCL-2 interaction and to increase cell death, enforcing a prosurvival role of the BAG-1 protein in AML. Interestingly, synergic cytotoxic effects of doxorubicin, VP16 drugs, and ABT-737 compound were observed when Thioflavin S was coupled with these drugs. Taken together, our results gave further proof that upregulation of BAG-1 plays a critical role in AML and that BAG-1 targeting might be considered for a combined therapeutic strategy with conventional chemotherapy drugs in the treatment of AML patients.
authors.affiliation: Women and Child Health Department, Hematology-Oncology Laboratory Istituto di Ricerca Pediatrica (IRP), University of Padova, Padova, Italy. Electronic address: sanja.aveic@unipd.it.
authors.forename: Sanja
authors.initials: S
authors.lastname: Aveic
authors.affiliation: Women and Child Health Department, Hematology-Oncology Laboratory Istituto di Ricerca Pediatrica (IRP), University of Padova, Padova, Italy.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
authors.affiliation: Women and Child Health Department, Hematology-Oncology Laboratory Istituto di Ricerca Pediatrica (IRP), University of Padova, Padova, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Accordi
authors.affiliation: Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'G. Gaslini', Genova, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Micalizzi
authors.affiliation: Department of Biomedicine in Childhood, University of Bari, Bari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.affiliation: Department of Pediatrics, "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Masetti
authors.affiliation: Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesù, University of Pavia, Pavia, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Women and Child Health Department, Hematology-Oncology Laboratory Istituto di Ricerca Pediatrica (IRP), University of Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Women and Child Health Department, Hematology-Oncology Laboratory Istituto di Ricerca Pediatrica (IRP), University of Padova, Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Pigazzi
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D052160:Benzothiazoles; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D016503:Drug Delivery Systems; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D013844:Thiazoles / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C091732:BCL2-associated athanogene 1 protein; D052160:Benzothiazoles; D004268:DNA-Binding Proteins; D013844:Thiazoles; D014157:Transcription Factors; C009462:thioflavin T