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

ABSTRACT

6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN or CD437), originally identified as a retinoic acid receptor γ-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 p21^WAF1/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 p21^WAF1/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.

ACKNOWLEDGMENTS

We thank S. Waldrop for preparation of the manuscript.

This work is in part supported by National Institute of Health grants CA51933 (M.I.D., X.-K.Z., and J.A.F.), CA60988 (X.-K.Z.), CA63783 and CA76173 (D.M.) and CA72994 (J.C.R.); Tobacco-Related Disease Research Program of California (6RT-0168 (X.-K.Z.) and GRT-0212 (M.I.D. and X.-K.Z.); California Breast Cancer Research Program 3PB-0018 (X.-K.Z.) and 3CB-0246 (D.M.); and U.S. Army Medical Research Program grant DAMD17-4440 (X.-K.Z.). A.A. was supported by a fellowship from the BCRP (University of California), and F.B. was supported by a fellowship from La Ligue Nationale Centre Le Cancer (Paris, France).