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Increased Retinoic Acid Responsiveness in Lung Carcinoma Cells that Are Nonresponsive Despite the Presence of Endogenous Retinoic Acid Receptor (RAR) ß by Expression of Exogenous Retinoid Receptors Retinoid X Receptor , RAR, and RAR¹

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are thought to mediate most of the effects of retinoids on cell growth and differentiation. Despite expressing abundant levels of RARß mRNA, lung adenocarcinoma H1792 cells are resistant to the growth-inhibitory effects of all-trans-retinoic acid, suggesting that they have a defect in retinoid signaling. To determine whether transfection of exogenous receptors can restore retinoid responsiveness, we transiently transfected into H1792 cells coexpression vectors containing cDNAs of cell surface antigen CD7 and either RAR, RARß, RAR, or RXR. The cells were then treated with retinoids and incubated with 5'-bromo-2'deoxyuridine. Cells that express exogenous receptor were identified using antibodies against CD7, and cells that synthesized DNA were identified with anti-5'-bromo-2'-deoxyuridine antibodies using secondary antibodies with red and green fluorescence, respectively. RXR and RAR enhanced growth inhibition by all-trans-retinoic acid or 9-cis-retinoic acid, whereas RAR was less effective, and RARß was ineffective. The effects of the transfected receptors were associated with antagonism of activator protein 1 (AP-1) activity. Studies with RXR deletion and point mutants indicated that growth suppression is: (a) dependent on intact DNA-binding and ligand-binding regions but not on the NH₂-terminal region, which contains a ligand-independent transactivation function; (b) dependent on RXR homodimer formation and transactivation of RXR response element; and (c) associated with AP-1 antagonism. These results demonstrate that transfected receptors can restore responsiveness to retinoids by antagonizing AP-1 in H1792 cells.

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