Upregulation of SOCS-1 by Nutlin-3 in acute myeloid leukemia cells but not in primary normal cells

Abstract

OBJECTIVE:It has been shown that SOCS-1 plays an important role in the proper control of cytokine/growth factor responses and acts as a tumor suppressor in acute myeloid leukemias. Therefore, the objective of the present study was to evaluate the in vitro effect of treatment with Nutlin-3, a small molecule inhibitor of the MDM2/p53 interaction, on the expression of the suppressor of cytokine signaling 1 in primary acute myeloid leukemia cells and in myeloid cell lines with differential p53 status.METHOD:The expression of the suppressor of cytokine signaling 1 was quantitatively analyzed by real-time PCR in myeloid p53wild-type (OCI and MOLM) and p53null HL-60, leukemic cell lines, in patient-derived acute myeloid leukemia blasts, and in primary normal cell types, such as macrophages, endothelial cells, and bone marrow mesenchymal stem cells. The p53-dependence of the suppressor of cytokine signaling 1 upregulation that is induced by Nutlin-3 was analyzed in experiments performed using siRNA for p53, while the functional upregulation of the suppressor of cytokine signaling 1 was analyzed by assessing the levels of phosphorylated STAT-3.RESULTS:Nutlin-3 significantly upregulated the transcription of the suppressor of cytokine signaling 1 in p53wild-type OCI and MOLM but not in p53deleted p53null HL60, myeloid leukemic cell lines, as well as in primary acute myeloid leukemia blasts. Conversely, and somewhat unexpectedly, Nutlin-3 did not modulate the suppressor of cytokine signaling 1 expression in primary normal macrophages, endothelial cells, and bone marrow mesenchymal stem cells. The p53-dependent upregulation of the suppressor of cytokine signaling 1 by Nutlin-3 was associated with the downregulation of phosphorylated STAT-3, a major molecular target of the suppressor of cytokine signaling 1.CONCLUSION:Overall, our data suggest a potential role for the suppressor of cytokine signaling 1 as a therapeutic target of Nutlin-3 in p53 wild-type acute myeloid leukemias.

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

“…It is also possible that SOCS1 prevents excessive stimulation of innate immunity when p53 is activated by a strong stress factor and the cells are additionally exposed to interferons (not unusual situation in lung epithelium for instance). It was found by others that SOCS1 can be upregulated by nutlin-3a (a specific p53 activator) in acute myeloid leukemia cells which also supports the notion that SOCS1 is p53-dependent gene [54]. Thus, the data presented in this paper and the observations made by others support the notion that the innate immunity is the stress-response system strongly influenced by p53.…”

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

“…In the context of hematological malignancies, our group has significantly contributed to the demonstration and characterization of the potential of Nutlin-3 in preclinical models based on established cell lines and patient-derived cells of acute myeloid leukemia (AML) and of chronic lymphocytic leukemia (CLL). In these settings, the efficacy of Nutlin-3 has been related to activation of P53 apoptotic pathway [ 75 , 76 ] and modulation of a specific panel of genes and proteins related to cell survival [ 77 – 80 ], apoptosis [ 81 , 82 ], and cell cycle progression [ 83 ]. Other groups validated the cytotoxic preclinical effects of Nutlin-3 in different hematological malignancies.…”

Resistance of human primary mesenchymal stem cells to cytotoxic effects of nutlin‐3 in vitro

“…These results support the argument that interventions using agents that affect cell cycle checkpoints, that is, nutlin-3, could potentially protect normal cells against hemotherapeutic effects while maintaining onco-toxicity. This may be due to the ability of nutlin-3 to inhibit uncontrolled proliferation of cancerous cells 48 and inducing reversible quiescence in normal cells. 22,[41][42][43] The present study assessed the mRNA expression of the cell cycle and apoptosis genes, and also functionally evaluated apoptosis.…”

“…47 The exact mechanism contributing to the different effects of nutlin-3 on normal and cancer cells is yet to be understood. This may be due to the ability of nutlin-3 to inhibit uncontrolled proliferation of cancerous cells 48 and inducing reversible quiescence in normal cells. 11,49 Further studies are therefore recommended to focus on understanding the molecular mechanisms of nutlin-3 in normal cells compared with in cancer cells.…”