7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia

• Published in: Cells (Basel, Switzerland) Switzerland), 2019-05, Vol.8 (5), p.482
• Main Authors: Paz, Jessica Liliane, Levy, Debora, Oliveira, Beatriz Araujo, de Melo, Thatiana Correia, de Freitas, Fabio Alessandro, Reichert, Cadiele Oliana, Rodrigues, Alessandro, Pereira, Juliana, Bydlowski, Sergio Paulo
• Format: Article
• Language: English
• Subjects: 7-KC; Acute myeloid leukemia; Adipocytes; Apoptosis; Apoptosis - drug effects; Autophagosomes - metabolism; Autophagy; Autophagy - drug effects; Bone marrow; Caspase 3 - metabolism; Caspase 8 - metabolism; Caspase-3; Caspase-8; Cell Cycle Checkpoints - drug effects; Cell death; Cell Death - drug effects; Cell differentiation; Cell growth; Cell Survival - drug effects; Cell viability; Cells, Cultured; Chemotherapy; Cholesterol; Cytoskeleton; Experiments; Hedgehog Proteins - metabolism; Hematopoietic stem cells; Humans; Ketocholesterols - pharmacology; Leukemia; Leukemia, Myeloid, Acute - pathology; Lipids; Membrane Potential, Mitochondrial - drug effects; mesenchymal stem cell; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Metabolism; Myeloid leukemia; Oxidative stress; Oxidative Stress - drug effects; oxysterol; Phagocytosis; Proteins; Reactive Oxygen Species - metabolism; S phase; Smoothened Receptor - metabolism; Stem cells
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells8050482

7-Ketocholesterol (7-KC) is a cholesterol oxidation product with several biological functions. 7-KC has the capacity to cause cell death depending on the concentration and specific cell type. Mesenchymal stem cells (MSCs) are multipotent cells with the ability to differentiate into various types of cells, such as osteoblasts and adipocytes, among others. MSCs contribute to the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases, such as leukemia, to a yet unknown extent. Here, we describe the effect of 7-KC on the death of bone marrow MSCs from patients with acute myeloid leukemia (LMSCs). LMSCs were less susceptible to the death-promoting effect of 7-KC than other cell types. 7-KC exposure triggered the extrinsic pathway of apoptosis with an increase in activated caspase-8 and caspase-3 activity. Mechanisms other than caspase-dependent pathways were involved. 7-KC increased ROS generation by LMSCs, which was related to decreased cell viability. 7-KC also led to disruption of the cytoskeleton of LMSCs, increased the number of cells in S phase, and decreased the number of cells in the G1/S transition. Autophagosome accumulation was also observed. 7-KC downregulated the SHh protein in LMSCs but did not change the expression of SMO. In conclusion, oxiapoptophagy (OXIdative stress + APOPTOsis + autophagy) seems to be activated by 7-KC in LMSCs. More studies are needed to better understand the role of 7-KC in the death of LMSCs and the possible effects on the SHh pathway.