Induction of retinoic acid receptor beta mediates growth inhibition in retinoid resistant human colon carcinoma cells

Background-The molecular mechanisms underlying the differential sensitivity of human colon carcinoma cells to retinoid mediated growth inhibition are poorly understood. Aim-To identify the intracellular mechanisms responsible for resistance aga inst retinoid mediated growth inhibition in human colon carcinoma cells. Methods-Anchorage independent growth of the human colon carcinoma cell line s HT29 and LoVo was determined by a human tumour clonogenic assay. Retinoid receptor expression was evaluated by reverse transcription polymerase chai n reaction and northern blotting. Retinoid mediated transactivation was ass essed by transient transfection of a pTK:beta REx2-luc reporter construct. Retinoid receptor overexpression was achieved by selecting stably transfect ed cell clones. Results-Retinoid treatment resulted in profound dose dependent growth inhib ition in HT29 cells, while LoVo cells were unaffected. The two cell lines e xpress identical patterns of nuclear retinoid receptor mRNA transcripts. Ho wever, on retinoid treatment, retinoic acid receptor beta gene expression w as upregulated only in retinoid sensitive HT29 cells, but not in retinoid r esistant LoVo cells. in accordance, stable overexpression of retinoic acid receptor beta but not a or gamma conferred retinoid mediated growth inhibit ion on LoVo cells. Conclusion-Induction of retinoic acid receptor beta expression is required and sufficent to confer retinoid mediated growth inhibition on human colon carcinoma cells.