Sphingomyelin synthase 1 activity is regulated by the BCR-ABL oncogene

Tara Ann Burns, Marimuthu Subathra, Paola Signorelli, Young Choi, Xiaofeng Yang, Yong Wang, Maristella Villani, Kapil Bhalla, Daohong Zhou, Chiara Luberto

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Sphingomyelin synthase (SMS) produces sphingomyelin while consuming ceramide (a negative regulator of cell proliferation) and forming diacylglycerol (DAG) (a mitogenic factor). Therefore, enhanced SMS activity could favor cell proliferation. To examine if dysregulated SMS contributes to leukemogenesis, we measured SMS activity in several leukemic cell lines and found that it is highly elevated in K562 chronic myelogenous leukemia (CML) cells. The increased SMS in K562 cells was caused by the presence of Bcr-abl, a hallmark of CML; stable expression of Bcr-abl elevated SMS activity in HL-60 cells while inhibition of the tyrosine kinase activity of Bcr-abl with Imatinib mesylate decreased SMS activity in K562 cells. The increased SMS activity was the result of up-regulation of the Sms1 isoform. Inhibition of SMS activity with D609 (a pharmacological SMS inhibitor) or down-regulation of SMS1 expression by siRNA selectively inhibited the proliferation of Bcr-abl-positive cells. The inhibition was associated with an increased production of ceramide and a decreased production of DAG, conditions that antagonize cell proliferation. A similar change in lipid profi le was also observed upon pharmacological inhibition of Bcr-abl (K526 cells) and siRNA-mediated down-regulation of BCR-ABL (HL-60/Bcr-abl cells). These fi ndings indicate that Sms1 is a downstream target of Bcr-abl, involved in sustaining cell proliferation of Bcr-abl-positive cells.

Original languageEnglish (US)
Pages (from-to)794-805
Number of pages12
JournalJournal of lipid research
Volume54
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • Ceramide
  • Diacylglycerol
  • Imatinib mesylate

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

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