ABSTRACT
The E3 ubiquitin ligase (E3) WWP1 is an oncogenic factor implicated in the maintenance of different types of epithelial cancers. The role of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) in haematological neoplasms remains unknown. Acute myeloid leukaemia (AML) is characterized by the expansion of malignant myeloid cells blocked at different stages of differentiation. Here we report that the expression of WWP1 is significantly augmented in a large cohort of primary AML patients and in AML cell lines, compared with haematopoietic cells from healthy donors. We show that WWP1 inactivation severely impairs the growth of primary AML blasts and cell lines in vitro. In vivo, we observed a reduced leukaemogenic potential of WWP1-depleted AML cells upon transplantation into immunocompromised mice. Mechanistically, WWP1 inactivation induces the accumulation of its protein substrate p27Kip1, which ultimately contributes to G0/G1 cell cycle arrest of AML blasts. In addition, WWP1 depletion triggers the autophagy signalling and reduces survival of leukaemic cells. Collectively, our findings provide molecular insights into the anti-cancer potential of WWP1 inhibition, suggesting that this E3 is a promising biomarker and druggable target in AML.
Subject(s)
Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Ubiquitin-Protein Ligases/metabolism , Animals , Cell Cycle Checkpoints/physiology , Cell Differentiation/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Cell Survival/physiology , Cyclin-Dependent Kinase Inhibitor p27/metabolism , G1 Phase/physiology , Gene Expression Regulation, Neoplastic/physiology , Humans , Mice , Resting Phase, Cell Cycle/physiology , Signal Transduction/physiology , U937 Cells , Ubiquitination/physiologyABSTRACT
The cytotoxic and anti-Mycobacterium tuberculosis H37Rv activities of hydro-alcoholic extract of Lannea acida A. Rich (Anacardiaceae) were assessed. The cytoxicity evaluation was carried out on THP1 monocytoid cell line (after 24 h at 1; 5 and 10 microg mL(-1)) and showed only a slight modification of lactate dehydrogenase (LDH) release. The rate of monocytes in different stages of mitosis had been amended in absence and presence of extract as follows: Go/G1 58.83-59.83%; synthesis 21.95-18.64%; mitosis 16.67-15.77%; necrosis 2.65-5.64%. The percentage of inhibition of Mycobacterium tuberculosis proliferation was respectively 77.6 and 36.8% at 1.2 and 0.6 mg mL(-1) of extract. This is an interesting experimental study on antimicrobial and immune-stimulating properties of Lannea acida ethanol-water (70% v/v) extract which may contain potential antibacterial and immune-stimulating agents for clinical use.
