Miltefosine suppression of Pten null T-ALL leukemia via β-catenin degradation through inhibition of pT308-Akt and TGFβ1/Smad3.

Abstract

Pten deletion in the hematopoietic stem cells (HSC) causes a myeloproliferative disorder, which may subsequently develop into a T-cell acute lymphoblastic leukemia (T-ALL). β-catenin expression was dramatically increased in the c-KitmidCD3+Lin- leukemia stem cells (LSC) and was critical for T-ALL development. Therefore, the inactivation of β-catenin in LSC may have a potential to eliminate the LSC. In this study, we investigated the mechanism of enhancement of the β-catenin expression and subsequently used a drug to inactivate β-catenin expression in T-ALL. Western blot (WB) analysis revealed an increased level of β-catenin in the leukemic cells, but not in the pre-leukemic cells. Furthermore, the WB analysis of the thymic cells from different stages of leukemia development showed that increased expression of β-catenin was not via the pS9-GSK3β signaling, but was dependent on the pT308-Akt activation. Miltefosine (Hexadecylphosphocholine) is the first oral anti-Leishmania drug, which is a phospholipid agent and has been shown to inhibit the PI3K/Akt activity. Treatment of the PtenΔ/Δ leukemic mice with Miltefosine for different durations demonstrated that the pT308-Akt and the β-catenin expressions were inhibited in the leukemia blast cells. Miltefosine treatment also suppressed the TGFβ1/Smad3 signaling pathway. Analysis of TGFβ1 in the sorted subpopulations of the blast cells showed that TGFβ1 was secreted by the CD3+CD4- subpopulation and may exert effects on the subpopulations of both CD3+CD4+ and CD3+CD4- leukemia blast cells. When a TGFβR1 inhibitor, SB431542 was injected into the PtenΔ/Δ leukemic mice, the Smad3 and β-catenin expressions were down-regulated. On the basis of the results, we conclude that Miltefosine can suppress leukemia by degrading β-catenin through repression of the pT308-Akt and TGFβ1/Smad3 signaling pathways. This study demonstrates a possibility to inhibit Pten loss-associated leukemia genesis via targeting Akt and Smad3.

• Authors: Yanmei Zhang, Sauhar Lee, Wei Xu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 524 Issue 4 Pg. 1018-1024 (04 16 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32063363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Smad3 Protein
• Transforming Growth Factor beta1
• beta Catenin
• Phosphorylcholine
• miltefosine
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Gene Deletion
• Humans
• Mice
• PTEN Phosphohydrolase (genetics)
• Phosphorylcholine (analogs & derivatives, pharmacology, therapeutic use)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism)
• Proteolysis (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• beta Catenin (metabolism)