Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss

Ortiz‐Lazareno, Pablo César; Bravo-Cuéllar, Alejandro; Lerma-Díaz, José Manuel; Jave‐Suárez, Luis Felipe; Aguilar‐Lemarroy, Adriana; Domínguez-Rodríguez, Jorge Ramiro; González-Ramella, Óscar; Célis, Ruth De; Gómez-Lomelí, Paulina; Hernández‐Flores, Georgina

doi:10.1186/1475-2867-14-13

Cited by 49 publications

(37 citation statements)

References 76 publications

(74 reference statements)

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“…Thus, the different modulation of the expression of genes belonging to the Bcl-2 family, with respect to single treatment, may account for the efficient routing of cells towards apoptosis exerted by the combined treatment with AZT plus an NF-kB inhibitor. A similar evidence was found to play a key role in increasing susceptibility to chemotherapeutic drugs in the case of treatment of U937 cells with doxorubicin (DOX), which caused the overexpression of p65, of Bcl-2 and Bcl-xL, in combination with the proteasome inhibitor MG 132 that reduced the DOXinduced p65 and Bcl-2 overexpression [34]. Moreover, similar mechanisms have been hypothesized for sensitization of human epidermoid carcinoma KCP-4 cells to cisplatin, through down-regulation of Bcl-2 and Bcl-xL, exerted by the NF-kB inhibitor curcumin [33].…”

Section: Discussionmentioning

confidence: 78%

Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB

et al. 2015

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Section: Discussionmentioning

confidence: 78%

Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB

et al. 2015

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“…Activated NF-κB seems to trigger a series of molecular reactions 24, 25. For instance, NF-κB can inhibit pro-apoptotic protein Bax and induce the expression of anti-apoptotic protein Bcl-2, which involved in chemotherapy induced apoptosis 26, 27.…”

Section: Introductionmentioning

confidence: 99%

Nucleophosmin Mutations Induce Chemosensitivity in THP-1 Leukemia Cells by Suppressing NF-κB Activity and Regulating Bax/Bcl-2 Expression

Zhang¹,

Qin²,

Yang³

et al. 2016

J. Cancer

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Nucleophosmin (NPM1) - a gene that encodes for a nuclear protein with multiple functions. Mutations in NPM1 are seen in approximately one-third of acute myeloid leukemia (AML) and are generally associated with good response to induction chemotherapy. However, the mechanisms underlying this chemosensitivity are still unknown. Recent studies have established that nuclear factor-κB (NF-κB) activation is a key response of leukemia cell to chemotherapy. In this study, we transfected human monocytic leukemia THP-1 cells with the vector expressing NPM1 mutation variant (NPM1mA), and confirmed overexpression of NPM1mA at mRNA and protein levels by reverse transcription PCR (RT-PCR) and immunohistochemistry, respectively. The effects of NPM1 mutations on chemotherapeutical agents induced apoptosis, NF-κB activity and gene expression were examined using flow cytometry, luciferase reporter assays, quantitative real time PCR (qRT-PCR) and Western blot. We found that overexpression of NPM1mA in THP-1 cells sensitized these cells to apoptosis induced by chemotherapeutical agents such as daunorubicin (DNR) and cytarabine (Ara-C). Moreover, we demonstrated that expression of NPM1 mA reduced the NF-κB transcription activity of THP-1 cells upon drug treatment. In addition, restoration of NF-κB activity via TNF-α stimulation could attenuate the effect of NPM1mA overexpression on DNR-and Ara-C-induced apoptosis. Interestingly, expression of NPM1mA could upregulate Bax and downregulate Bcl-2 at mRNA and protein levels in THP-1 cells when treated with DNR or Ara-C. We also demonstrated that restoration of NF-κB activity via TNF-α pre-treatment reversed the effect of NPM1mA on the Bax/Bcl-2 expression. Furthermore, evaluation of gene expression data from The Cancer Genome Atlas (TCGA) dataset revealed that NPM1-mutated patients showed a higher expression of Bax and a lower expression of Bcl-2. These results suggest that the NPM1 gene mutations could confer increased sensitivity to chemotherapeutic agents, at least in part, by suppressing NF-κB activity and regulating Bax/Bcl-2 expression.

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“…Furthermore, knockdown or inhibition of TRPM2 in neuroblastoma, breast and prostate cancer cell lines resulted in decreased proliferation and was synergistic with chemotherapy (14–17). Induction of NF-κB by doxorubicin has been reported as a resistance mechanism to chemotherapy in a myelomonocytic AML cell line (18). This raises the possibility that modulating TRPM2 signaling could increase the effect of standard chemotherapy in AML cells while sparing normal hematopoietic stem and early progenitor compartments.…”

Section: Introductionmentioning

confidence: 99%

Transient potential receptor melastatin-2 (Trpm2) does not influence murine MLL-AF9-driven AML leukemogenesis or in vitro response to chemotherapy

Haladyna

Pastuer

Riedel

et al. 2016

Experimental Hematology

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Transient potential receptor melastatin-2 (TRPM2) is a non-selective cationic, Ca2+ permeable transmembrane pore that is preferentially expressed in cells of the myeloid lineage, and modulates signaling pathways converging onto NF-kB. This is of potential interest for AML therapy, as NF-κB signaling is emerging as a key pathway mediating drug resistance and leukemia initiating cell survival in AML, and inhibition of NF-κB signaling has been shown to be synergistic with chemotherapy. TRPM2 is overexpressed in AML compared to normal bone marrow, with highest levels in the FAB M3-6 subtypes. To determine the effect of loss of Trpm2 in a defined genetic model, we established MLL-AF9 driven AML on a Trpm2−/− genetic background. Trpm2−/− MLL-AF9 leukemias displayed reduced NF-κB phosphorylation and nuclear translocation. In vivo primary and secondary recipients of Trpm2−/− MLL-AF9 leukemias showed increased latency compared to recipients of wild type leukemia cells. However, the difference in latency was small, and lost in tertiary transplants. The effect of loss of Trpm2 in a BCR-ABL/NUP98-HOXA9 fusion model was even smaller. Given reports that loss or inhibition of TRPM2 enhanced killing by DNA damaging agents in neuroblastoma, breast and prostate cancer cell lines, we exposed Trpm2−/− and Trpm2wt primary MLL-AF9 leukemias to doxorubicin, cytarabine and etoposide, but found no difference in IC50. The in vitro response to decitabine was also unaffected. In summary, TRPM2 does not seem to play a major role in myeloid leukemogenesis. In addition, loss of TRPM2 does not augment the cytotoxicity of standard AML chemotherapeutic agents.

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Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss

Cited by 49 publications

References 76 publications

Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB

Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB

Nucleophosmin Mutations Induce Chemosensitivity in THP-1 Leukemia Cells by Suppressing NF-κB Activity and Regulating Bax/Bcl-2 Expression

Transient potential receptor melastatin-2 (Trpm2) does not influence murine MLL-AF9-driven AML leukemogenesis or in vitro response to chemotherapy

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