Effects Of Retinoids On Human Cancer Cells

In order to better understand the mechanisms that underlie the antiproliferative effects of retinoids and RA induced differentiation/apoptosis, we have examined the response of human carcinoma cell lines to all-trans retinoic acid (ATRA) and N-(4-hydroxyphenyl) retinamide (4HPR) in terms of cell growth, apoptosis and regulation of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mRNA. GLC82 (lung adenocarcinoma), BGC823 (stomach adenocarcinoma), and EC109. In order to better understand the mechanisms that underlie the antiproliferative effects of EC109 (esophageal squamous carcinoma) cells were treated with 10μM of ATRA or 4HPR for various length of time and analyzed. The results show that growth inhibition by ATRA and 4HPR in GLC82 and BGC823 cells correlates with the induction of RARP2 gene, whereas ATRA resistance in EC109 cells parallels the loss of RARP2 inducibility. Exogenous RARP2 expression does not restore the ATRA responsiveness in EC109 cells, but enhance 4HPR-induced growth inhibition, suggesting that 4HPR act at least in part via the RARβ receptor. We speculate that the loss of RARp2 inducibility in EC109 cells may be due to a still unknown repressor, which could be a regulator of ATRA biological activity.We have further identified the changes of gene expression patterns which underlie the RA induced differentiation/apoptosis in GLC82 cells, by employing mRNA differential display. Two genes which were differentially expressed before and after ATRA treatment have been partly cloned, and one corresponds to a sequence known gene DPH2L with unknown function, which was first isolated from the critical region of deletion on chromosome 17p13.3 in human ovarian carcinoma, and regarded as a candidate tumor suppressor gene. Our results provide evidence that the DPH2L gene is widely expressed in various kinds of human...