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Mol Cell Biol, August 1998, p. 4719-4731, Vol. 18, No. 8
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Molecular Determinants of AHPN (CD437)-Induced Growth Arrest and Apoptosis in Human Lung Cancer Cell Lines

Yin Li,1 Bingzhen Lin,1 Anissa Agadir,1 Ru Liu,1 Marcia I. Dawson,2 John C. Reed,1 Joseph A. Fontana,3 Frédéric Bost,4 Peter D. Hobbs,2 Yun Zheng,1 Guo-quan Chen,1 Braham Shroot,5 Dan Mercola,4 and Xiao-kun Zhang1 *

The Burnham Institute, Cancer Research Center, La Jolla, California 920371; Retinoid Program, SRI International, Menlo Park, California 940252; Marilyn and Stuart Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland 212013; Sidney Kimmel Cancer Center, San Diego, California 921214; and Centre International de Researches Dermatologiques (CIRD), Galderma, Valbonne, France5

Received 27 August 1997/Returned for modification 30 October 1997/Accepted 19 February 1998

6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN or CD437), originally identified as a retinoic acid receptor gamma -selective retinoid, was previously shown to induce growth inhibition and apoptosis in human breast cancer cells. In this study, we investigated the role of AHPN/CD437 and its mechanism of action in human lung cancer cell lines. Our results demonstrated that AHPN/CD437 effectively inhibited lung cancer cell growth by inducing G0/G1 arrest and apoptosis, a process that is accompanied by rapid induction of c-Jun, nur77, and p21WAF1/CIP1. In addition, we found that expression of p53 and Bcl-2 was differentially regulated by AHPN/CD437 in different lung cancer cell lines and may play a role in regulating AHPN/CD437-induced apoptotic process. On constitutive expression of the c-JunAla(63,73) protein, a dominant-negative inhibitor of c-Jun, in A549 cells, nur77 expression and apoptosis induction by AHPN/CD437 were impaired, whereas p21WAF1/CIP1 induction and G0/G1 arrest were not affected. Furthermore, overexpression of antisense nur77 RNA in A549 and H460 lung cancer cell lines largely inhibited AHPN/CD437-induced apoptosis. Thus, expression of c-Jun and nur77 plays a critical role in AHPN/CD437-induced apoptosis. Together, our results reveal a novel pathway for retinoid-induced apoptosis and suggest that AHPN/CD437 or analogs may have a better therapeutic efficacy against lung cancer.

* Corresponding author. Mailing address: The Burnham Institute, Cancer Research Center, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 646-3141. Fax: (619) 646-3195. E-mail: xzhang{at}burnham-inst.org.

Mol Cell Biol, August 1998, p. 4719-4731, Vol. 18, No. 8
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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