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Cellular and Molecular Biology Letters

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Volume 20, Issue 4


Elevated pressure enhanced TRAIL-induced apoptosis in hepatocellular carcinoma cells via ERK1/2-inactivation

Eunyoung Hong
  • Department of Preventive Medicine, School of Medicine, Korea University, Seoul, Korea
  • Department of Public Health, Graduate School of Medicine, Korea University, Seoul, Korea
  • Other articles by this author:
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/ Eunil Lee
  • Corresponding author
  • Department of Preventive Medicine, School of Medicine, Korea University, Seoul, Korea
  • Department of Public Health, Graduate School of Medicine, Korea University, Seoul, Korea
  • Email
  • Other articles by this author:
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/ Joonhee Kim / Daeho Kwon
  • Department of Microbiology, College of Medicine, Catholic Kwandong University, Gangneung, Korea
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/ Yongchul Lim
  • Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • Other articles by this author:
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Published Online: 2015-10-15 | DOI: https://doi.org/10.1515/cmble-2015-0030


The high frequency of intrinsic resistance to TNF-related apoptosisinducing ligand (TRAIL) in tumor cell lines has necessitated the development of strategies to sensitize tumors to TRAIL-induced apoptosis. We previously showed that elevated pressure applied as a mechanical stressor enhanced TRAIL-mediated apoptosis in human lung carcinoma cells in vitro and in vivo. This study focused on the effect of elevated pressure on the sensitization of TRAIL-resistant cells and the underlying mechanism. We observed elevated pressure-induced sensitization to TRAIL-mediated apoptosis in Hep3B cells, accompanied by the activation of several caspases and the mitochondrial signaling pathway. Interestingly, the enhanced apoptosis induced by elevated pressure was correlated with suppression of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation and CREB without any change to other MAPKs. Phosphorylation of Bcl-2-associated death promoter (BAD) also decreased, leading to inhibition of the mitochondrial pathway. To confirm whether the activation of pERK1/2 plays a key role in the TRAIL-sensitizing effect of elevated pressure, Hep3B cells were pre-treated with the ERK1/2-specific inhibitor PD98059 instead of elevated pressure. Co-treatment with PD98059 and TRAIL augmented TRAIL-induced apoptosis and decreased BAD phosphorylation. The inhibition of ERK1/2 activation by elevated pressure and PD98059 also reduced BH3 interacting-domain death agonist (BID), thereby amplifying apoptotic stress at the mitochondrial level. Our results suggest that elevated pressure enhances TRAIL-induced apoptosis of Hep3B cells via specific suppression of ERK1/2 activation among MAPKs.

This article offers supplementary material which is provided at the end of the article.

Keywords : TRAIL; Elevated pressure; Mechanical stress; ERK1/2; Hepatocellular carcinoma; Apoptosis; BAD; CREB


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About the article

Received: 2014-08-16

Accepted: 2015-06-17

Published Online: 2015-10-15

Published in Print: 2015-12-01

Citation Information: Cellular and Molecular Biology Letters, Volume 20, Issue 4, Pages 535–548, ISSN (Online) 1689-1392, DOI: https://doi.org/10.1515/cmble-2015-0030.

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