PPM1D Knockdown Suppresses Cell Proliferation, Promotes Cell Apoptosis, and Activates p38 MAPK/p53 Signaling Pathway in Acute Myeloid Leukemia

Abstract

Objectives: This study was to explore the effect of protein phosphatase, Mg2+/Mn2+ dependent 1D knockdown on proliferation and apoptosis as well as p38 MAPK/p53 signaling pathway in acute myeloid leukemia. Methods: The expression of protein phosphatase, Mg2+/Mn2+ dependent 1D was detected in acute myeloid leukemia cell lines including SKM-1, KG-1, AML-193, and THP-1 cells, and normal bone marrow mononuclear cells isolated from healthy donors. The knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D was conducted by transfecting small interfering RNA into AML-193 cells and KG-1 cells. Results: The relative messenger RNA/protein expressions of protein phosphatase, Mg2+/Mn2+ dependent 1D were higher in SKM-1, KG-1, AML-193, and THP-1 cells compared with control cells (normal bone marrow mononuclear cells). After transfecting protein phosphatase, Mg2+/Mn2+ dependent 1D small interfering RNA into AML-193 cells and KG-1 cells, both messenger RNA and protein expressions of protein phosphatase, Mg2+/Mn2+ dependent 1D were significantly reduced, indicating the successful transfection. Most importantly, knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D suppressed cell proliferation and promoted cell apoptosis in AML-193 cells and KG-1 cells. In addition, knockdown of protein phosphatase, Mg2+/Mn2+ dependent 1D enhanced the expressions of p-p38 and p53 in AML-193 cells and KG-1 cells. The above observation suggested that protein phosphatase, Mg2+/Mn2+ dependent 1D knockdown suppressed cell proliferation, promoted cell apoptosis, and activated p38 MAPK/p53 signaling pathway in acute myeloid leukemia cells. Conclusion: Protein phosphatase, Mg2+/Mn2+ dependent 1D is implicated in acute myeloid leukemia carcinogenesis, which illuminates its potential role as a treatment target for acute myeloid leukemia.

Wild-type p53-induced phosphatase sensitizes acute myeloid leukemia cells to conventional chemotherapy

“…Then we tested the toxicity of GSK2830371 (GSK), a highly specific WIP1 inhibitor, on those two AML cell lines in a biologically relevant range of concentrations from 0.1 uM to 5 uM. In contrast with previously published studies on the toxicity of WIP1 RNA interference in AML cells (Li et al, 2020), we did not observe the negative effect of WIP1 phosphatase activity inhibition on cell viability when a chemical inhibitor was used as monotherapy. At the same time, the combination of GSK2830371 with Cytosar significantly potentiated the efficiency of chemotherapy in OCI-AML2 cells but not in Mono-Mac-1 cells, which are resistant to Cytosar (Fig.…”

“…Other researchers used RNA interference to deplete WIP1 in several AML cell lines. They showed that reducing WIP1 levels with siRNA to protein phosphatase, Mg 2+ /Mn 2+ dependent 1D suppressed cell proliferation and promoted cell apoptosis in AML-193 cells and KG-1 cells (Li et al, 2020).…”

Revealing key lncRNAs in cytogenetically normal acute myeloid leukemia by reconstruction of the lncRNA–miRNA–mRNA network

“…6 ). Pathway analysis showed that lncRNA XIST related mRNAs were significantly enriched in 16 pathway terms including ‘PI3K-Akt signaling pathway’, ‘FoxO signaling pathway’, ‘p53 signaling pathway’ 24 and ‘Ras signaling pathway’, all of which have been shown to play important roles in AML. LncRNA TUG1 related mRNAs were significantly enriched in 12 pathway terms including ‘PI3K-Akt signaling pathway’, ‘FoxO signaling pathway’, and ‘Ras signaling pathway’, all of which have also been shown to play important roles in AML.…”

Revealing key lncRNAs in cytogenetically normal acute myeloid leukemia by reconstruction of the lncRNA–miRNA–mRNA network based on the competitive endogenous RNA theory

“…Acute myeloid leukemia(AML) is the most common type of acute leukemia in adults. According to the WHO classi cation,patients with recurring cytogenetic abnormalities,such as t (8,21), inv(16)(p13q22) or t (15,17) often had a better prognosis [16].But for those with normal karyotype,there is an another story.…”

“…The key three lncRNAs(XIST,GABPB1-AS1,TUG1) and their linked miRNAs/mRNAs were extracted and used to reconstruct the new subnetworks as follows(Figure 5). Pathway analysis showed that LncRNA XIST related mRNA were signi cantly enriched in 16 pathway terms including 'PI3K-Akt signaling pathway','FoxO signaling pathway', 'p53 signaling pathway' [15] and 'Ras signaling pathway', all of which had been shown to play important roles in AML.LncRNA GABPB1-AS1 related mRNA were signi cantly enriched in 6 pathway terms including 'PI3K-Akt signaling pathway' and 'Pathways in cancer'pathway terms.LncRNA TUG1 related mRNA were signi cantly enriched in 12 pathway terms including 'PI3K-Akt signaling pathway','FoxO signaling pathway',and 'Ras signaling pathway',all of which had been shown to play important roles in AML.…”