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Molecular Pharmacology

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Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

Joo-Yun Byun, Min-Jung Kim, Da-Young Eum, Chang-Hwan Yoon, Woo-Duck Seo, Ki Hun Park, Jin-Won Hyun, Yun-Sil Lee, Jae-Seong Lee, Moon-Young Yoon and Su-Jae Lee
Molecular Pharmacology October 2009, 76 (4) 734-744; DOI: https://doi.org/10.1124/mol.109.056259
Joo-Yun Byun
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Min-Jung Kim
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Da-Young Eum
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Chang-Hwan Yoon
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Woo-Duck Seo
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Ki Hun Park
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Jin-Won Hyun
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Yun-Sil Lee
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Jae-Seong Lee
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Moon-Young Yoon
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Su-Jae Lee
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Abstract

Naturally occurring triterpenoid compounds have long been used as anti-inflammatory, antimalarial, and insecticidal agents. It has become evident that some of the natural or synthetic triterpenoids have promising clinical potential as both a therapeutic and chemopreventive agent for cancer. However, the molecular basis for the antitumor activity of triterpenoid has yet to be defined. In this study, we show that pristimerin, a natural triterpenoid, induces mitochondrial cell death in human cervical cancer cells and that reactive oxygen species (ROS)-dependent activation of both Bax and poly(ADP-ribose) polymerase-1 (PARP-1) is critically required for the mitochondrial dysfunction. We also showed that c-Jun N-terminal kinase (JNK) is involved in ROS-dependent Bax activation. Treatment of pristimerin induced an increase in intracellular ROS, JNK activation, conformational change, and mitochondrial redistribution of Bax, mitochondrial membrane potential loss, and cell death. The PARP-1 was also found to be activated by pristimerin treatment. An antioxidant, N-acetyl-l-cysteine (NAC), inhibited pristimerin-induced JNK activation, Bax relocalization, and PARP-1 activation, as well as mitochondrial cell death. Moreover, inhibition of JNK clearly suppressed conformational change and mitochondrial translocation of Bax and subsequent mitochondrial cell death but did not affect PARP-1 activation. Inhibition of PARP-1 with 1,5-dihydroxyisoquinoline (DIQ) or with small interfering RNA of PARP-1 significantly attenuated pristimerin-induced mitochondrial membrane potential loss and cell death but did not affect JNK activation and Bax relocalization. These results indicate that the natural triterpenoid pristimerin induces mitochondrial cell death through ROS-dependent activation of both Bax and PARP-1 in human cervical cancer cells and that JNK is involved in ROS-dependent Bax activation.

  • JNK, c-Jun N-terminal kinase
  • MAPK, mitogen-activated protein kinase
  • siRNA, small interfering RNA
  • PI, propidium iodide
  • PARP, poly(ADP-ribose) polymerase
  • DiOC6(3), 3,3′dihexylocarbocyanine iodide
  • DIQ, 1,5-dihydroxyisoquinoline
  • ROS, reactive oxygen species
  • NAC, N-acetyl-l-cysteine
  • ERK, extracellular signal-regulated kinase
  • PAR, poly(ADP-ribose)
  • HSP60, 60-kDa heat shock protein
  • PBS, phosphate-buffered saline
  • DCFH-DA, 2,7-dichlorodihydrofluorescein diacetate
  • AIF, apoptosis-inducing factor
  • si, small interfering
  • DCF, 2′,7′-dichlorofluorescein diacetate
  • Trx, thioredoxin
  • z-VAD-fmk, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone
  • SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
  • PD98059, 2′-amino-3′-methoxyflavone
  • SP600125, anthra[1,9-cd]pyrazol-6(2H)-one.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Basic Atomic Energy Research Institute, Ministry of Science and Technology of Korea [Nuclear R&D Programs Grant].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • ABBREVIATIONS:

  • J.B. and M.K. contributed equally to this work.

    • Received March 16, 2009.
    • Accepted July 2, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (4)
Molecular Pharmacology
Vol. 76, Issue 4
October 2009
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Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

Joo-Yun Byun, Min-Jung Kim, Da-Young Eum, Chang-Hwan Yoon, Woo-Duck Seo, Ki Hun Park, Jin-Won Hyun, Yun-Sil Lee, Jae-Seong Lee, Moon-Young Yoon and Su-Jae Lee
Molecular Pharmacology October 1, 2009, 76 (4) 734-744; DOI: https://doi.org/10.1124/mol.109.056259

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Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

Joo-Yun Byun, Min-Jung Kim, Da-Young Eum, Chang-Hwan Yoon, Woo-Duck Seo, Ki Hun Park, Jin-Won Hyun, Yun-Sil Lee, Jae-Seong Lee, Moon-Young Yoon and Su-Jae Lee
Molecular Pharmacology October 1, 2009, 76 (4) 734-744; DOI: https://doi.org/10.1124/mol.109.056259
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