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Apoptosis of PC12 cells by 4-hydroxy-2-nonenal is mediated through selective activation of the c-Jun N-terminal

B J Song1, Y Soh, M Bae

  • 1Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 12420 Parklawn Drive, 20852, Rockville, MD, USA. bjs@mail.nih.gvo

Chemico-Biological Interactions
|April 18, 2001
PubMed

Insights

Cytotoxic lipid peroxides like 4-hydroxy-2-nonenal (HNE) trigger apoptosis via the SEK1-JNK pathway. This study elucidates HNE-induced cell death mechanisms, highlighting JNK activation in PC12 cells.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Toxicology

Background:

  • Cytotoxic lipid peroxides, such as 4-hydroxy-2-nonenal (HNE), are implicated in cellular damage from toxic chemicals.
  • The precise mechanisms by which HNE induces apoptosis remain incompletely understood.
  • Mitogen-activated protein (MAP) kinases are crucial in cellular signaling pathways relevant to cell death.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying HNE-induced apoptosis in PC12 cells.
  • To identify the specific MAP kinase pathways involved in HNE-mediated cell death.
  • To elucidate the role of the SEK1-JNK pathway in HNE-induced apoptosis.

Main Methods:

  • PC12 cells were treated with HNE, and the activation of MAP kinases (JNK, ERK, p38) was measured.
  • SEK1 and JNK pathway activation was further examined using transient transfection of wild-type and dominant-negative mutants in COS-7 cells.
  • The effects of a survival-promoting agent and a p38 inhibitor on HNE-induced apoptosis and JNK activation were assessed.

Main Results:

  • HNE treatment rapidly and transiently activated c-Jun N-terminal protein kinase (JNK) and its upstream kinase SEK1 within minutes.
  • Extracellular signal-regulated kinase (ERK) and p38 MAP kinase activities remained unchanged.
  • Inhibition of SEK1 or JNK activation significantly reduced HNE-induced cell death, while p38 inhibition had no effect.
  • A survival agent blocked both HNE-induced JNK activation and apoptosis.

Conclusions:

  • HNE-induced apoptosis in PC12 cells is primarily mediated by the selective activation of the SEK1-JNK signaling pathway.
  • The ERK and p38 MAP kinase pathways are not significantly involved in HNE-induced apoptosis.
  • This study clarifies a key molecular mechanism of HNE-induced cellular toxicity.

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