Retinoic acid downregulates growth, fibronectin and RARα in 3T3 cells: Ha-ras blocks this response and RA metabolism

Retinoic acid (RA) reduced growth, fibronectin, and retinoic acid receptor (RARα) in NIH 3T3 cells but not in cells transformed by the Ha-ras oncogene. RA lowered RARα transcript and protein, increased RARβ transcripts, and had no effect on RARγ. H-ras transformation downregulated RAR expression and abolished responsiveness to RA. Ha-ras-transformed cells were as active as normal NIH-3T3 cells in RA uptake but were unable to degrade it to medium oxidation products, so that, paradoxically, the resistant cells accumulated 20-30-fold as much RA as the sensitive cells. RA sensitivity/insensitivity correlated with RA metabolism/lack thereof in 15 cell lines in serum-free medium. These data suggest a relationship between RA inhibition of cell growth and intracellular RA metabolism.