Induction of apoptosis via mitogen-activated protein kinase pathway by a K vitamin analog in rat hepatocytes

Ziqiu Wang, Yuji Nishikawa, Meifang Wang, Brian I. Carr

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background/Aims: Compound 5 (Cpd 5), a vitamin K analog, inhibits rat hepatocyte DNA synthesis and hepatoma cell growth. The aim of this study was to determine if the inhibitory effect of Cpd 5 on cell growth was related to apoptosis. Methods: Isolated rat hepatocytes were cultured with Cpd 5, and mitogen-activated signaling pathway and apoptosis pathway were investigated using Western blot analysis. Results: When rat hepatocytes were cultured with Cpd 5 for 48 h, apoptosis was evident, which included characteristic morphological changes, DNA fragmentation, and the activation of caspase 3 (CPP 32)-like protease. Examination of upstream events of apoptosis pathway showed that the expression of Bax was induced and bcl-2 was inhibited by Cpd 5 treatment. Concomitant with the induction of apoptosis, Cpd 5 activated the extracellular signal-regulated kinase (ERK) signaling pathway. PD 98059, a mitogen-activated protein kinase kinase inhibitor, and glutathione, an anti-thiol-oxidant, not only blocked Cpd 5-induced ERK phosphorylation, but also antagonized the activation of CPP-32, the altered Bcl-2/Bax expression, and DNA fragmentation. Conclusions: The data suggest that the ERK signaling pathway may be involved in the regulation of rat hepatocyte apoptosis induced by Cpd 5.

Original languageEnglish
Pages (from-to)85-92
Number of pages8
JournalJournal of Hepatology
Volume36
Issue number1
DOIs
Publication statusPublished - 2002

Fingerprint

Vitamin K
Mitogen-Activated Protein Kinases
Hepatocytes
Apoptosis
Mitogen-Activated Protein Kinase 7
DNA Fragmentation
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Growth
Mitogens
Sulfhydryl Compounds
Oxidants
Caspase 3
Glutathione
Hepatocellular Carcinoma
Peptide Hydrolases
Western Blotting
Phosphorylation
DNA

Keywords

  • Apoptosis
  • K vitamin
  • Mitogen-activated protein kinase
  • Rat hepatocyte

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Induction of apoptosis via mitogen-activated protein kinase pathway by a K vitamin analog in rat hepatocytes. / Wang, Ziqiu; Nishikawa, Yuji; Wang, Meifang; Carr, Brian I.

In: Journal of Hepatology, Vol. 36, No. 1, 2002, p. 85-92.

Research output: Contribution to journalArticle

Wang, Ziqiu ; Nishikawa, Yuji ; Wang, Meifang ; Carr, Brian I. / Induction of apoptosis via mitogen-activated protein kinase pathway by a K vitamin analog in rat hepatocytes. In: Journal of Hepatology. 2002 ; Vol. 36, No. 1. pp. 85-92.
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AB - Background/Aims: Compound 5 (Cpd 5), a vitamin K analog, inhibits rat hepatocyte DNA synthesis and hepatoma cell growth. The aim of this study was to determine if the inhibitory effect of Cpd 5 on cell growth was related to apoptosis. Methods: Isolated rat hepatocytes were cultured with Cpd 5, and mitogen-activated signaling pathway and apoptosis pathway were investigated using Western blot analysis. Results: When rat hepatocytes were cultured with Cpd 5 for 48 h, apoptosis was evident, which included characteristic morphological changes, DNA fragmentation, and the activation of caspase 3 (CPP 32)-like protease. Examination of upstream events of apoptosis pathway showed that the expression of Bax was induced and bcl-2 was inhibited by Cpd 5 treatment. Concomitant with the induction of apoptosis, Cpd 5 activated the extracellular signal-regulated kinase (ERK) signaling pathway. PD 98059, a mitogen-activated protein kinase kinase inhibitor, and glutathione, an anti-thiol-oxidant, not only blocked Cpd 5-induced ERK phosphorylation, but also antagonized the activation of CPP-32, the altered Bcl-2/Bax expression, and DNA fragmentation. Conclusions: The data suggest that the ERK signaling pathway may be involved in the regulation of rat hepatocyte apoptosis induced by Cpd 5.

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