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Osmotic stress sensitizes naturally resistant cells to TNF-alpha-induced apoptosis

D L Franco1, I M Nojek, L Molinero

  • 1Laboratorio de Fisiología y Biología Molecular, Departamento de Cs. Biológicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, C1428EHA Bs. As., Argentina.

Cell Death and Differentiation
|September 17, 2002
PubMed

Insights

Osmotic stress sensitizes resistant HeLa cells to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis by affecting kinase activity and Bcl-2 expression. This cell death occurs independently of enhanced NF-kappaB activation.

Area of Science:

  • Cell biology
  • Molecular biology
  • Apoptosis research

Background:

  • Cells are typically resistant to TNF-alpha-induced cell death.
  • Resistance can be overcome by blocking NF-kappaB or inhibiting protein synthesis.
  • The role of osmotic stress in sensitizing cells to TNF-alpha is not fully understood.

Purpose of the Study:

  • To investigate the role of osmotic stress in TNF-alpha-induced cell death.
  • To elucidate the molecular mechanisms underlying osmotic stress-mediated sensitization to apoptosis.

Main Methods:

  • Utilized HeLa cells, a naturally resistant cell line.
  • Applied osmotic stress in conjunction with TNF-alpha treatment.
  • Analyzed kinase activity, Bcl-2 expression, and NF-kappaB activation.
  • Investigated the effects of p38 kinase inhibition.

Main Results:

  • Osmotic stress sensitizes HeLa cells to TNF-alpha-induced apoptosis.
  • Sensitization involves increased kinase activity and decreased Bcl-2 expression.
  • A late increase in NF-kappaB activation was observed, but cell death proceeded independently.
  • Inhibition of p38 kinase exacerbated the effects of osmotic stress on TNF-alpha-induced cell death.

Conclusions:

  • Osmotic stress is a potent sensitizer of TNF-alpha-induced apoptosis in resistant cells.
  • The mechanism involves modulation of key apoptotic regulators including kinases and Bcl-2.
  • NF-kappaB activity does not prevent cell death under these conditions and its inhibition can enhance apoptosis.
  • p38 kinase plays a critical role in the interplay between osmotic stress and TNF-alpha signaling in apoptosis.

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