Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia
Most patients with acute myeloid leukaemia (AML) experience disease recurrence after chemotherapy largely due to the development of drug resistance. Small extracellular vesicles (sEVs) are known to play a significant role in leukaemia drug resistance by delivery of anti-apoptotic proteins and genes...
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Online Access: | http://dx.doi.org/10.1080/20013078.2020.1800979 |
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doaj-6007a404fa05460b886e5362e531307b2020-11-25T04:06:38ZengTaylor & Francis GroupJournal of Extracellular Vesicles2001-30782020-01-019110.1080/20013078.2020.18009791800979Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemiaChang-Sook Hong0Emily Jeong1Michael Boyiadzis2Theresa L. Whiteside3University of Pittsburgh School of MedicineTaylor Allderdice High SchoolUPMC Hillman Cancer CenterUniversity of Pittsburgh School of MedicineMost patients with acute myeloid leukaemia (AML) experience disease recurrence after chemotherapy largely due to the development of drug resistance. Small extracellular vesicles (sEVs) are known to play a significant role in leukaemia drug resistance by delivery of anti-apoptotic proteins and genes conferring resistance to recipient cells. sEV levels are elevated in AML patients’ plasma at the time of diagnosis and remain elevated in complete remission after chemotherapy. The mechanism of enhanced sEV secretion in AML is unknown. We speculated that cholesterol synthesis by AML blasts may be related to elevated sEV secretion. Intracellular levels of cholesterol and of HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), the rate-limiting enzyme in cholesterol synthesizing mevalonate pathway, significantly increased in cultured AML cells or primary human non-malignant cells treated with cytarabine or decitabine. Concomitantly, levels of sEVs produced by these cells also increased. Treatment with an HMGCR inhibitor, Simvastatin, or siRNAs targeting HMGCR blocked the chemotherapy-induced enhancement of sEV secretion in AML cells. sEVs carry HMGCR and chemotherapy enhances HMGCR levels in sEVs. HMGCR+ sEVs upregulate intracellular cholesterol and promote AML cell proliferation. A pharmacologic blockade of HMGCR emerges as a potential future therapeutic option for disrupting sEV signalling leading to cholesterol-driven chemo-resistance in AML.http://dx.doi.org/10.1080/20013078.2020.1800979leukaemiachemotherapycholesterolhmgcrsmall extracellular vesicles |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chang-Sook Hong Emily Jeong Michael Boyiadzis Theresa L. Whiteside |
spellingShingle |
Chang-Sook Hong Emily Jeong Michael Boyiadzis Theresa L. Whiteside Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia Journal of Extracellular Vesicles leukaemia chemotherapy cholesterol hmgcr small extracellular vesicles |
author_facet |
Chang-Sook Hong Emily Jeong Michael Boyiadzis Theresa L. Whiteside |
author_sort |
Chang-Sook Hong |
title |
Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia |
title_short |
Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia |
title_full |
Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia |
title_fullStr |
Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia |
title_full_unstemmed |
Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia |
title_sort |
increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia |
publisher |
Taylor & Francis Group |
series |
Journal of Extracellular Vesicles |
issn |
2001-3078 |
publishDate |
2020-01-01 |
description |
Most patients with acute myeloid leukaemia (AML) experience disease recurrence after chemotherapy largely due to the development of drug resistance. Small extracellular vesicles (sEVs) are known to play a significant role in leukaemia drug resistance by delivery of anti-apoptotic proteins and genes conferring resistance to recipient cells. sEV levels are elevated in AML patients’ plasma at the time of diagnosis and remain elevated in complete remission after chemotherapy. The mechanism of enhanced sEV secretion in AML is unknown. We speculated that cholesterol synthesis by AML blasts may be related to elevated sEV secretion. Intracellular levels of cholesterol and of HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), the rate-limiting enzyme in cholesterol synthesizing mevalonate pathway, significantly increased in cultured AML cells or primary human non-malignant cells treated with cytarabine or decitabine. Concomitantly, levels of sEVs produced by these cells also increased. Treatment with an HMGCR inhibitor, Simvastatin, or siRNAs targeting HMGCR blocked the chemotherapy-induced enhancement of sEV secretion in AML cells. sEVs carry HMGCR and chemotherapy enhances HMGCR levels in sEVs. HMGCR+ sEVs upregulate intracellular cholesterol and promote AML cell proliferation. A pharmacologic blockade of HMGCR emerges as a potential future therapeutic option for disrupting sEV signalling leading to cholesterol-driven chemo-resistance in AML. |
topic |
leukaemia chemotherapy cholesterol hmgcr small extracellular vesicles |
url |
http://dx.doi.org/10.1080/20013078.2020.1800979 |
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