Opposing Effects of Retinoic Acid on Cell Growth Result from Alternate Activation of Two Different Nuclear Receptors

The yin and yang of retinoic acid signalling.

The vitamin A metabolite retinoic acid is a potent anti-carcinogenic agent.  It is in current use in treatment of certain leukemias, and is being tested for treatment of other cancers. Suppression of carcinoma cell growth by retinoic acid stems from the ability of this compound to activate a transcription factor called the retinoic acid receptor (RAR). Once activated, RAR induces the expression of proteins that inhibit cell growth and trigger cell death. However, in some tissues and some cancers, retinoic acid displays an opposing activity: it promotes cell survival and proliferation. The basis for the dual activity of retinoic acid has long remained unclear. In a recent issue of Cell (Schug et al., Cell, 129:723–733, 2007), Noy and her colleagues show that, in addition to functioning through RAR, retinoic acid activates another transcription factor, termed PPARβ/δ. Unlike RAR, this transcription factor induces the expression of proteins that signal for cell survival and proliferation. In addition, the observations reveal that the partitioning of retinoic acid between the two receptors that mediate its dual transcriptional activities is controlled by small lipid-binding proteins, cellular retinoic acid-binding protein II and fatty acid binding protein 5, that capture retinoic acid in the cytosol and selectively deliver it to nuclear RAR and PPARβ/δ, respectively. Consequently, retinoic acid activates RAR to inhibit growth in cells with a high content of CRABP-II, but it signals through PPARβ/δ and promotes survival in cells that highly express FABP5. These observations point at novel targets for potential interventions in therapy of some cancers.