Differential effects of retinoic acid on growth and apoptosis in human colon cancer cell lines associated with the induction of retinoic acid receptor beta

Retinoids are well known as potential chemopreventive and chemotherapeutic agents against a variety of human cancers. Here, we report that retinoic ac id (RA) induced differential growth inhibition in human colon cancer cell l ines: while DLD-1, HT-29, and WiDr were relatively resistant, HCT-15 and Co lo201 were relatively sensitive. All-trims-retinoic acid caused morphologic al and biochemical changes such as membrane shrinkage, chromatin condensati on, and DNA cleavage, which are typical features of cells undergoing apopto sis in sensitive cell lines. Although retinoic acid receptor (RAR)alpha, be ta, gamma and retinoid X receptor alpha were expressed in all cell lines ex amined, a significant induction of RAR beta by all-trans-RA was observed on ly in sensitive cell lines, suggesting important roles of RAR beta in RA se nsitivity. When a vector containing the RAR beta gene was introduced into a relatively resistant cell line, DLD-1, the cells acquired RA sensitivity. Further, we found that the RAR beta transfectants of DLD-1 expressed an enh anced level of c-Myc and Bar proteins, which may result in the increased su sceptibility of the cells to all-trans-RA-induced apoptosis. In summary, ou r data demonstrated that RA induced growth inhibition and apoptosis in huma n colon cancer cells and that the induction of RAR beta may mediate the ret inoid action. (C) 2000 Elsevier Science Inc.