EVIDENCE OF A RETINOID SIGNALING ALTERATION INVOLVING THE ACTIVATOR PROTEIN-1 COMPLEX IN TUMORIGENIC HUMAN BRONCHIAL EPITHELIAL-CELLS AND NONSMALL CELL LUNG-CANCER CELLS

Retinoids, including retinol and retinoic acid derivatives, inhibit th e growth of normal human bronchial epithelial (HBE) cells. Using a lun g carcinogenesis model consisting of normal, immortalized, and tumorig enic HBE cells, we showed previously that, compared to normal HBE cell s, the tumorigenic HBE cell line 1170I is resistant to the growth-inhi bitory effects of all-trans-retinoic acid (t-RA). Retinoid receptor fu nction is preserved in tumorigenic 1170I cells, suggesting that other retinoid signaling components are altered. The activator protein 1 (AP -1) complex is a component of the retinoid signaling pathway and has d emonstrated importance in cellular growth and differentiation, Therefo re, we investigated whether AP-1 is involved in a retinoid signaling d efect in tumorigenic 1170I cells and in retinoid-resistant non-small c ell lung cancer (NSCLC) cell lines. We found that t-RA treatment inhib ited AP-1 transcriptional activity in normal HBE cells but not in tumo rigenic 1170I cells nor in the NSCLC cell lines Calu-1, Calu-6, SKMES- 1, and ChaGo K1. We sought mechanisms for this retinoid signaling alte ration involving AP-1 in tumorigenic 1170I cells, nasal AP-1 transcrip tional activity; AP-1 DNA-binding activity; and the mRNA levels of c-f os, the AP-1 coactivator Jun activation domain-binding protein 1, and the retinoid receptor corepressor, the silencing mediator for retinoid and thyroid hormone receptors (SMRT), were lower in tumorigenic 1170I cells than in normal HBE cells, Transient transfection of tumorigenic 1170I cells with c-fos or CREB binding protein, which is a coactivato r of AP-1 and retinoid receptors, enhanced basal AP-1 transcriptional activity but did not alter the effects of t-RA on AP-1 transcriptional activity. These findings provide evidence of a retinoid signaling alt eration involving AP-1 in tumorigenic 1170I and NSCLC cells. Furthermo re, the inhibitory effect of t-RA on AP-1 transcriptional activity was not restored in tumorigenic 1170I cells by transfection of c-fos, sil encing mediator for retinoid and thyroid hormone receptors, Jun activa tion domain-binding protein 1, or CREB-binding protein, suggesting the involvement of other transcriptional coregulators in this retinoid si gnaling defect.