Evidence that retinoic acid receptor β induction by retinoids is important for tumor cell growth inhibition

Retinoic acid receptor beta (RAR beta) is thought to be involved in suppressing cell growth and tumorigenicity. Many premalignant and malignant cells exhibit a reduced RAR beta expression. However, in some of these cells (e.g. H157 human squamous cell carcinoma cells), RAR beta can be induced by retinoids (e.g. all-trans-retinoic acid, ATRA) because its promoter contains a retinoic acid response element. To examine the hypothesis that RAR beta induction is important for inhibition of cell proliferation by retinoids, we blocked ATRA-induced RAR beta expression in H157 cells using a retroviral vector harboring multiple copies of antisense RAR beta 2 sequences. Antisense RAR beta-transfected cells showed not only decreased expression of ATRA-induced RAR beta protein but also reduced ATRA-induced RAR beta binding activity and transactivation. Importantly, all antisense RAR beta transfectants of H157 cells were less responsive than vector-transfected cells to the growth inhibitory effects of the retinoids ATRA and Ch55 in vitro. These results demonstrate that RAR beta induction may play an important role in mediating growth inhibitory effects of retinoids in cancer cells.