RESEARCH ARTICLE

p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells

  • Xiao-Xi Guo 1,2 ,
  • Yang Li 1 ,
  • Chao Sun 1 ,
  • Dan Jiang 1 ,
  • Ying-Jia Lin 1 ,
  • Feng-Xie Jin 3 ,
  • Seung-Ki Lee 4 ,
  • Ying-Hua Jin , 1
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  • 1. Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun 130012, China
  • 2. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
  • 3. College of Bio and Food Technology, Dalian Polytechnic University, Dalian 116034, China
  • 4. College of Pharmacy and the Research Institute for Pharmaceutical Science, Seoul National University, Seoul 157-742, Republic of Korea

Received date: 13 Dec 2013

Accepted date: 12 Jan 2014

Published date: 23 Jun 2014

Copyright

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

We have recently reported that Ginsenoside Rh2 (G-Rh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-nonmutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for antitumor drug development.

Key words: G-Rh2; Fas; p53; apoptosis

Cite this article

Xiao-Xi Guo , Yang Li , Chao Sun , Dan Jiang , Ying-Jia Lin , Feng-Xie Jin , Seung-Ki Lee , Ying-Hua Jin . p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells[J]. Protein & Cell, 2014 , 5(3) : 224 -234 . DOI: 10.1007/s13238-014-0027-2

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