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

Abstract

The molecular mechanisms underlying the differential sensitivity of human colon carcinoma cells to retinoid mediated growth inhibition are poorly understood.To identify the intracellular mechanisms responsible for resistance against retinoid mediated growth inhibition in human colon carcinoma cells.Anchorage independent growth of the human colon carcinoma cell lines HT29 and LoVo was determined by a human tumour clonogenic assay. Retinoid receptor expression was evaluated by reverse transcription polymerase chain reaction and northern blotting. Retinoid mediated transactivation was assessed by transient transfection of a pTK::betaREx2-luc reporter construct. Retinoid receptor overexpression was achieved by selecting stably transfected cell clones.Retinoid treatment resulted in profound dose dependent growth inhibition in HT29 cells, while LoVo cells were unaffected. The two cell lines express identical patterns of nuclear retinoid receptor mRNA transcripts. However, on retinoid treatment, retinoic acid receptor beta gene expression was upregulated only in retinoid sensitive HT29 cells, but not in retinoid resistant LoVo cells. In accordance, stable overexpression of retinoic acid receptor beta but not alpha or gamma conferred retinoid mediated growth inhibition on LoVo cells.Induction of retinoic acid receptor beta expression is required and sufficent to confer retinoid mediated growth inhibition on human colon carcinoma cells.