MOLECULAR DETERMINANTS OF AHPN (CD437)-INDUCED GROWTH ARREST AND APOPTOSIS IN HUMAN LUNG-CANCER CELL-LINES

6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHP N or CD437), originally identified as a retinoic acid receptor gamma-s elective retinoid, was previously shown to induce growth inhibition an d apoptosis in human breast cancer cells. In this study, we investigat ed the role of AHPN/CD437 and its mechanism of action in human lung ca ncer cell lines. Our results demonstrated that AHPN/CD437 effectively inhibited lung cancer cell growth by inducing G(0)/G(1) arrest and apo ptosis, a process that is accompanied by rapid induction of c-Jun, nur 77, and p21(WAF1/CIP1). In addition, we found that expression of p53 a nd 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, wherea s p21(WAF1/CIP1) induction and G(0)/G(1) arrest were not affected. Fur thermore, overexpression of antisense nar77 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-in duced apoptosis. Together, our results reveal a novel pathway for reti noid-induced apoptosis and suggest that AHPN/CD437 or analogs may have a better therapeutic efficacy against lung cancer.