Targeting BAG-1: a novel strategy to increase drug efficacy in acute myeloid leukemia

Sanja Aveic; Giampietro Viola; Benedetta Accordi; Concetta Micalizzi; Nicola Santoro; Riccardo Masetti; Franco Locatelli; Giuseppe Basso; Martina Pigazzi

doi:10.1016/j.exphem.2014.10.016

Targeting BAG-1: a novel strategy to increase drug efficacy in acute myeloid leukemia

Exp Hematol. 2015 Mar;43(3):180-190.e6. doi: 10.1016/j.exphem.2014.10.016. Epub 2014 Nov 11.

Authors

Sanja Aveic¹, Giampietro Viola², Benedetta Accordi², Concetta Micalizzi³, Nicola Santoro⁴, Riccardo Masetti⁵, Franco Locatelli⁶, Giuseppe Basso², Martina Pigazzi²

Affiliations

¹ Women and Child Health Department, Hematology-Oncology Laboratory Istituto di Ricerca Pediatrica (IRP), University of Padova, Padova, Italy. Electronic address: sanja.aveic@unipd.it.
² Women and Child Health Department, Hematology-Oncology Laboratory Istituto di Ricerca Pediatrica (IRP), University of Padova, Padova, Italy.
³ Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'G. Gaslini', Genova, Italy.
⁴ Department of Biomedicine in Childhood, University of Bari, Bari, Italy.
⁵ Department of Pediatrics, "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
⁶ Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesù, University of Pavia, Pavia, Rome, Italy.

PMID: 25461257
DOI: 10.1016/j.exphem.2014.10.016

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / therapeutic use
Benzothiazoles
Child
Child, Preschool
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism*
Drug Delivery Systems*
Drug Therapy, Combination
Gene Expression Regulation, Neoplastic
Gene Silencing
Humans
Infant
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Thiazoles / therapeutic use*
Transcription Factors / genetics*
Transcription Factors / metabolism*

Substances

Antineoplastic Agents
BCL2-associated athanogene 1 protein
Benzothiazoles
DNA-Binding Proteins
Thiazoles
Transcription Factors
thioflavin T