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The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients.

ABSTRACT: The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth, and survival under physiological conditions. However, aberrant PI3K/Akt/mTOR signaling has been implicated in many human cancers, including acute myelogenous leukemia (AML). Therefore, the PI3K/Akt/mTOR network is considered as a validated target for innovative cancer therapy. The limit of acceptable toxicity for standard polychemotherapy has been reached in AML. Novel therapeutic strategies are therefore needed. This review highlights how the PI3K/Akt/mTOR signaling axis is constitutively active in AML patients, where it affects survival, proliferation, and drug-resistance of leukemic cells including leukemic stem cells. Effective targeting of this pathway with small molecule kinase inhibitors, employed alone or in combination with other drugs, could result in the suppression of leukemic cell growth. Furthermore, targeting the PI3K/Akt/mTOR signaling network with small pharmacological inhibitors, employed either alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit pharmacological inhibitors of the PI3K/Akt/mTOR cascade which show efficacy and safety in the clinical setting are now underway.

SUBMITTER: Martelli AM

PROVIDER: S-EPMC2911128 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Acute myelogenous leukemia (AML) is nosocomial with the highest pediatric mortality rates and a relatively poor prognosis. C4.4A(LYPD3) is a tumorigenic and high-glycosylated cell surface protein that has been proven to be linked with the carcinogenic effects in solid tumors, but no hematologic tumors have been reported. We focus on exploring the molecular mechanism of LYPD3 in the regulation of the occurrence and development of AML to provide a research basis for the screening of markers related to the treatment and prognosis. Methods: Datasets on RNA Sequencing (RNA-seq) and mRNA expression profiles of 510 samples were obtained from The Cancer Genome Atlas Program/The Genotype-Tissue Expression (Tcga-gtex) on 10 March 2021, which included the information on 173 AML tumorous tissue samples and 337 normal blood samples. The differential expression, identification of prognostic genes based on the COX regression model, and LASSO regression were analyzed. In order to better verify, experiments including gene knockdown mediated by small interfering RNA (siRNA), cell proliferation assays, and Western blot were prefomed. We studied the possible associated pathways through which LYPD3 may have an impact on the pathogenesis and prognosis of AML by gene set enrichment analysis (GSEA). Results: A total of 11,490 differential expression genes (DEGs) were identified. Among them, 4,164 genes were upregulated, and 7,756 genes were downregulated. The univariate Cox regression analysis and LASSO regression analysis found that 28 genes including LYPD3, DNAJC8, and other genes were associated with overall survival (OS). After multivariate Cox analysis, a total of 10 genes were considered significantly correlated with OS in AML including LYPD3, which had a poor impact on AML (p <0.05). The experiment results also supported the above conclusion. We identified 25 pathways, including the E2F signaling pathway, p53 signaling pathway, and PI3K_AKT signaling pathway, that were significantly upregulated in AML samples with high LYPD3 expression (p < 0.05) by GSEA. Further, the results of the experiment suggested that LYPD3 participates in the development of AML through the p53 signaling pathway or/and PI3K/AKT signaling pathway. Conclusion: This study first proved that the expression of LYPD3 was elevated in AML, which was correlated with poor clinical characteristics and prognosis. In addition, LYPD3 participates in the development of AML through p53 or/and the PI3K/AKT signaling pathway.

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The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients.

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