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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 22, 2007; DOI: 10.1124/jpet.107.126193

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Received for publication May 30, 2007.
Revised August 21, 2007.
Accepted for publication August 21, 2007.

Activation of NAG-1 via ERK1/2 mitogen-activated protein kinase revealed a isochaihulactone-triggered apoptotic pathway in human lung cancer A549 cells

Yi Lin Chen 1, Po Cheng Lin 2, Shee Ping Chen 3, Chai Ching Lin 4, Nu Man Tsai 5, Yeung Leung Cheng 6, Wen Liang Chang 7, Shinn Zong Lin 8, Horng Jyh Harn 9*

1 Graduate Institute of Biotechnology, National Ilan University, Ilan, Taiwan 2 Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Ta 3 Institute of Medical Sciences, Buddhist Tzu-Chi University, Hualien, Taiwan 4 Department of Applied Animal Science, National Ilan University, Ilan, Taiwan. 5 School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan 6 Division of Thoracic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 7 School of Pharmacy, National Defense Medical Center, Taipei, Taiwan 8 Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan 9 Department of Pathology, China Medical University and Hospital, Taichung, Taiwan

* Address correspondence to: E-mail: duke{at}tzuchi.com.tw

Abstract

The novel lignan isochaihulactone inhibits cell proliferation and is an effective inducer of apoptosis in a variety of carcinoma cell lines. To determine the mechanisms underlying these effects, we examined isochaihulactone-induced changes in gene expression using oligodeoxynucleotide-based microarray screening of a human lung carcinoma cell line, A549 cells. Isochaihulactone-inducible genes included the EGR-1 and NAG-1. Isochaihulacone increased EGR-1 and then NAG-1 mRNA and protein expression. Pure isochaihulactone induced phosphorylation of ERK1/2. Isochaihulactone-induced increases in EGR-1 and NAG-1 expression were reduced by the MEK1/2 inhibitor PD98059 and this effect was not blocked by the PI3K/AKT pathway inhibitor LY294002. Inhibition of isochaihulactone-induced NAG-1 expression by EGR-1 siRNA blocked isochaihulactone-induced apoptosis in A549 cells, suggesting that induction of EGR-1 expression decreases survival of A549 cells. RNA interference using double-stranded RNA specific for the NAG-1 gene also inhibited isochaihulactone-induced apoptosis and cells transfected to increased NAG-1 expression had a greater apoptotic response to isochaihulactone and reduced colony formation efficiency. In addition, treatment of the nude mice with isochaihulactone increased the in vivo NAG-1 expression as examined by immunohistochemistry from tumor biopsy. Isochaihulactone treatment increased the luciferase activity of NAG-1 in A549 cells transfected with the NAG-1 promoter construct. This induction increased expression of NAG-1 with p53 independent and Sp1 dependent. Our findings suggest that NAG-1 expression is up-regulated by isochaihulactone through an ERK-dependent pathway involving the activation of EGR-1.


Key words: RNA interference, apoptosis, extracellular signal-regulated kinase1/2, isochaihulactone, nonsteroidal anti-inflammatory drug-activated gene, oligodeoxynucleotide-based microarray




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