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Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells

Xiao-Yun Liu1, Yue-Feng Yang, Chu-Tse Wu

  • 1Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.

Biochemical and Biophysical Research Communications
|February 16, 2010
PubMed

Insights

Spred2, a negative regulator of the Ras-ERK pathway, inhibits chronic myeloid leukemia (CML) cell growth and survival. Imatinib treatment increases Spred2, suggesting Spred2 is a potential therapeutic target for CML.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Spreds are negative regulators of the Ras-extracellular signal-regulated kinase (ERK) pathway.
  • Their role in hematologic neoplasms, particularly chronic myeloid leukemia (CML), is largely unknown.
  • The impact of Spreds on signaling pathways related to Ras-ERK requires further investigation.

Purpose of the Study:

  • To investigate the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells.
  • To explore the potential of Spred2 as a therapeutic target in CML.

Main Methods:

  • Adenovirus-mediated Spred2 over-expression in CML cells.
  • Assessment of Ras-ERK cascade inhibition.
  • Evaluation of sphingosine kinase-1 (SPHK1) and Mcl-1 expression.
  • Analysis of cell proliferation and apoptosis.
  • Investigation of imatinib-induced Spred2 expression in K562 and primary CML cells.
  • Spred2 silencing using stable RNA interference.

Main Results:

  • Spred2 over-expression inhibited both constitutive and stem cell factor (SCF)-stimulated SPHK1 and Mcl-1 expression.
  • Spred2 over-expression inhibited CML cell proliferation and induced apoptosis.
  • Imatinib treatment increased endogenous Spred2 expression in K562 and primary CML cells.
  • Spred2 silencing partially protected K562 cells from imatinib-induced apoptosis.

Conclusions:

  • Spred2 plays a significant role in imatinib-induced cytotoxicity in CML cells.
  • Spred2 may exert its effects by inhibiting the Ras-ERK cascade and pro-survival molecules SPHK1 and Mcl-1.
  • Spred2 represents a potential therapeutic target for selective CML treatment.

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