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Published on: January 7, 2019
Sphingomyelin synthase 1 activity is regulated by the BCR-ABL oncogene
Tara Ann Burns1, Marimuthu Subathra1, Paola Signorelli2
1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.
Journal of Lipid Research
|November 20, 2012
Summary
Sphingomyelin synthase 1 (SMS1) drives leukemia cell proliferation by increasing diacylglycerol and decreasing ceramide. Inhibiting SMS1 or Bcr-abl halts cancer cell growth, suggesting SMS1 as a therapeutic target in chronic myelogenous leukemia (CML).
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Sphingomyelin synthase (SMS) activity influences cell proliferation by modulating ceramide and diacylglycerol (DAG) levels.
- Dysregulated SMS activity is implicated in various cancers, but its role in leukemogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of SMS in chronic myelogenous leukemia (CML) and its potential link to the Bcr-abl oncoprotein.
- To determine if SMS activity is a viable therapeutic target for CML.
Main Methods:
- SMS activity was measured in leukemic cell lines, including K562 (CML) and HL-60 cells.
- The effect of Bcr-abl expression and inhibition (using Imatinib mesylate) on SMS activity was assessed.
- SMS1 isoform expression was analyzed.
- SMS activity was inhibited using D609 or SMS1 expression was reduced via siRNA.
- Cell proliferation, ceramide, and DAG levels were measured following SMS or Bcr-abl inhibition.
Main Results:
- SMS activity was significantly elevated in K562 CML cells, correlating with Bcr-abl presence.
- Bcr-abl expression increased SMS activity, while Bcr-abl inhibition decreased it, indicating Bcr-abl upregulates SMS1.
- Inhibition of SMS or SMS1 by D609 or siRNA selectively reduced proliferation in Bcr-abl-positive cells.
- SMS inhibition led to increased ceramide and decreased DAG, counteracting proliferation, mirroring effects of Bcr-abl inhibition.
Conclusions:
- SMS1 is a downstream target of Bcr-abl and plays a crucial role in sustaining the proliferation of Bcr-abl-positive leukemia cells.
- Targeting SMS1 offers a potential therapeutic strategy for CML by disrupting the Bcr-abl signaling pathway and restoring anti-proliferative lipid profiles.
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