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.
Targeting BAG-1: A novel strategy to increase drug efficacy in acute myeloid leukemia / Aveic, Sanja; Viola, Giampietro; Accordi, Benedetta; Micalizzi, Concetta; Santoro, Nicola; Masetti, Riccardo; Locatelli, Franco; Basso, Giuseppe; Pigazzi, Martina. - In: EXPERIMENTAL HEMATOLOGY. - ISSN 0301-472X. - ELETTRONICO. - 43:3(2015), pp. 180-190. [10.1016/j.exphem.2014.10.016]
Targeting BAG-1: A novel strategy to increase drug efficacy in acute myeloid leukemia
MASETTI, RICCARDO;BASSO, GIUSEPPE;
2015
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
