Regulation of RARβ expression by RAR- and RXR-selective retinoids in human lung cancer cell lines: Effect on growth inhibition and apoptosis induction

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Abstract
Retinoids regulate the growth and differentiation of human tracheobronchial epithelial cells. In this study, we investigated the effects of all‐trans‐retinoic acid (trans‐RA) and receptor class‐selective retinoids on the growth and apoptosis of human lung cancer cell lines. Trans‐RA significantly inhibited the growth of Calu‐6 and H460 cells, accompanied by induction of RA receptor (RAR)β expression. In contrast, it had little effect on the growth of H292, SK‐MES‐1 and H661 lung cancer cell lines, in which RARβ expression was not induced. Stable expression of RARβ in RARβ‐negative, trans‐RA‐resistant SK‐MES‐1 and H661 lung cancer cells led to recovery of trans‐RA‐induced growth inhibition, which occurred, however, only at low serum concentration. Using fluorescent microscopy and the terminal deoxyribonucleotidyl transferase (TdT) assay, we demonstrated that induction of apoptosis by trans‐RA contributed to its growth‐inhibitory effect in trans‐RA‐sensitive lung cancer cell lines. Analysis of RAR‐selective and retinoid X receptor (RXR)‐selective retinoids showed that activation of both RARs and RXRs could induce growth inhibition in trans‐RA‐sensitive lung cancer cells. Also, an additive synergistic effect on growth inhibition and RARβ induction was observed when cells were treated with combinations of RAR‐selective and RXR‐selective retinoids. Together, our results show that expression of RARβ plays a role in mediating retinoid response in lung cancer cells and that activation of RARs or RXRs contributes to induction of RARβ, growth inhibition and apoptosis by retinoids. Int. J. Cancer 75:88–95, 1998.

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