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Activation of ERK during DNA damage-induced apoptosis involves protein kinase Cdelta

Alakananda Basu1, Haidi Tu

  • 1Department of Molecular Biology and Immunology, Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. abasu@hsc.unt.edu

Biochemical and Biophysical Research Communications
|July 26, 2005
PubMed

Insights

Protein kinase C (PKC) and extracellular signal-regulated kinases (ERKs) regulate cisplatin-induced apoptosis. Cisplatin activates ERK1/2 via PKCdelta, suggesting a role in DNA damage response and chemoresistance.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Protein kinase C (PKC) regulates apoptosis.
  • Extracellular signal-regulated kinases (ERKs) are involved in DNA damage response.
  • The relationship between PKC, ERKs, and cisplatin-induced apoptosis requires further elucidation.

Purpose of the Study:

  • To investigate the role of the ERK signaling pathway downstream of PKC in cisplatin-induced apoptosis.
  • To determine the specific PKC isoform involved in this pathway.
  • To explore the implications of this pathway in cisplatin-resistant cells.

Main Methods:

  • Utilized PKC activators (PDBu) and inhibitors (bisindolylmaleimide, Gö 6983, rottlerin) to assess ERK1/2 phosphorylation.
  • Employed MEK inhibitor U0126 to block ERK activation.
  • Investigated cisplatin-induced apoptosis and ERK activation in HeLa and cisplatin-resistant HeLa/CP cells.
  • Used siRNA to deplete PKCdelta and assess its effect on ERK activation.

Main Results:

  • PKC activation by PDBu led to ERK1/2 phosphorylation, inhibited by general PKC inhibitors and U0126.
  • Cisplatin induced concentration-dependent ERK1/2 activation in HeLa cells.
  • ERK2 levels were reduced in cisplatin-resistant HeLa/CP cells.
  • Inhibition of MEK (U0126) or PKCdelta (rottlerin, siRNA) suppressed cisplatin-induced ERK activation and cell death.

Conclusions:

  • Cisplatin-induced DNA damage activates ERK1/2 signaling through PKCdelta.
  • This PKCdelta-ERK pathway plays a crucial role in regulating cisplatin-induced apoptosis.
  • Understanding this pathway may offer insights into overcoming cisplatin resistance.

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