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PKCdelta mediates Nrf2-dependent protection of neuronal cells from NO-induced apoptosis

Jindan Zhang1, Amos C Hung, Poh Yong Ng

  • 1Cell Death and Human Disease Group, Division of Cancer and Developmental Cell Biology, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Republic of Singapore.

Biochemical and Biophysical Research Communications
|July 1, 2009
PubMed

Insights

Protein kinase C delta (PKCdelta) protects neuronal cells from nitric oxide (NO)-induced apoptosis. This study identifies PKCdelta as a key modulator of the Nrf2 signaling pathway, crucial for cellular defense against NO toxicity.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Nitric oxide (NO) plays a complex role in neuronal function, capable of both signaling and inducing toxicity.
  • The Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a critical cellular defense mechanism against oxidative stress.

Purpose of the Study:

  • To investigate the signaling pathways involved in Nrf2 activation by nitric oxide (NO).
  • To identify key modulators of NO-induced Nrf2/ARE-dependent gene expression and their role in neuronal cell survival.

Main Methods:

  • Screening of a chemical inhibitor library to identify compounds affecting NO-induced Nrf2 activation.
  • Utilizing ARE-luciferase reporter assays, Western blotting, and gene knockdown/overexpression techniques in neuronal cell lines (SH-Sy5y, SH-EP) and primary cortical neurons.
  • Assessing apoptosis induction and cell death in response to NO treatment under various experimental conditions.

Main Results:

  • Rottlerin, a protein kinase C delta (PKCdelta) inhibitor, reduced NO-induced Nrf2/ARE reporter activity and the expression of Nrf2 targets (NQO1, HO-1).
  • Rottlerin sensitized neuronal cells to NO-induced apoptosis, while PKCdelta overexpression protected cells and enhanced HO-1 induction.
  • PKCdelta knockdown or knockout increased sensitivity to NO-induced apoptosis and reduced HO-1 expression, confirming PKCdelta's protective role.

Conclusions:

  • Protein kinase C delta (PKCdelta) acts as a positive modulator of the NO-induced Nrf2/ARE signaling pathway in neuronal cells.
  • PKCdelta plays a crucial role in counteracting NO-mediated apoptosis, thereby protecting neuronal cells from NO-induced toxicity.

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