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Tumor necrosis factor-alpha-stimulated cell proliferation is mediated through sphingosine kinase-dependent Akt

Julie Radeff-Huang1, Tammy M Seasholtz, Jenny W Chang

  • 1Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.

The Journal of Biological Chemistry
|November 23, 2006
PubMed

Insights

Tumor necrosis factor-alpha (TNF-alpha) activates sphingosine kinase (SphK) to promote glioblastoma cell proliferation. SphK signaling, particularly through Akt activation and cyclin D expression, is crucial for this TNF-alpha-driven growth.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine involved in inflammation and cell death.
  • Sphingosine kinase (SphK) signaling pathways are implicated in various cellular processes, including proliferation.
  • The precise role of SphK in mediating TNF-alpha's effects on cell proliferation remains incompletely understood.

Purpose of the Study:

  • To investigate the role of SphK activity in TNF-alpha-stimulated proliferation of 1321N1 glioblastoma cells.
  • To elucidate the specific signaling mechanisms by which SphK mediates TNF-alpha's proliferative effects.

Main Methods:

  • Pharmacological inhibition of SphK using specific inhibitors.
  • Small interfering RNA (siRNA) mediated knockdown of SphK1.
  • Assessment of DNA synthesis, RhoA activation, ERK phosphorylation, Akt phosphorylation, and cyclin D expression.
  • Use of C3 exoenzyme and Y27632 to inhibit Rho proteins and Rho kinase, respectively.
  • Pertussis toxin treatment to assess the involvement of Gi-coupled S1P receptors.

Main Results:

  • SphK inhibition significantly reduced TNF-alpha-stimulated DNA synthesis in glioblastoma cells.
  • Neither RhoA nor ERK activation were identified as SphK-dependent mediators of TNF-alpha-induced proliferation.
  • TNF-alpha-stimulated Akt phosphorylation was attenuated by SphK inhibition or SphK1 knockdown.
  • TNF-alpha-induced cyclin D expression was dependent on both SphK and Akt.
  • Cell surface Gi-coupled S1P receptors were not involved in mediating TNF-alpha's effects on proliferation, ERK, or Akt phosphorylation.

Conclusions:

  • SphK-dependent Akt activation is a critical pathway in TNF-alpha-induced cell proliferation.
  • SphK signaling contributes to cyclin D expression, driving glioblastoma cell growth.
  • These findings highlight SphK as a potential therapeutic target in TNF-alpha-mediated cancers.

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