MyJournals Home  

RSS FeedsChemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells [Research Articles] (Journal of Lipid Research)


1 september 2019 17:00:50

Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells [Research Articles] (Journal of Lipid Research)

The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapy-selected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In description, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth. Digg Facebook Google StumbleUpon Twitter
43 viewsCategory: Cell Biology, Molecular Biology
Lysophosphatidylcholine-induced mitochondrial fission contributes to collagen production in human cardiac fibroblasts [Research Articles] (Journal of Lipid Research)
Heritability of apolipoprotein (a) traits in two-generational African-American and Caucasian families [Patient-Oriented and Epidemiological Research] (Journal of Lipid Research)
blog comments powered by Disqus
The latest issues of all your favorite science journals on one page


Register | Retrieve


Molecular Biology

Use these buttons to bookmark us: Digg Facebook Google StumbleUpon Twitter

Valid HTML 4.01 Transitional
Copyright © 2008 - 2020 Indigonet Services B.V.. Contact: Tim Hulsen. Read here our privacy notice.
Other websites of Indigonet Services B.V.: Nieuws Vacatures News Tweets Travel Photos Nachrichten Indigonet Finances Leer Mandarijn