Decryption of the retinoid death code in leukemia

The recent elucidation of several molecular paradigms by which retinoids regulate growth, differentiation, and apoptosis highlights their promise as drugs for cancer therapy and prevention. Several novel signaling pathways by which retinoids induce cell death have been identified recently. They comprise (a) the induction by RARalpha-selective retinoids of the tumor-selective death ligand TRAIL that kills acute promyelocytic leukemia (APL) cells in a paracrine mode of action, which is the cause of retinoic acid-induced apoptosis after maturation; (b) a novel RARalpha-independent rexinoid-PKA cross-talk that induces maturation of both ATRA-sensitive and ATRA-resistant APL cells and does not invoke ligand-induced alteration of PML-RARalpha signaling, stability, or compartmentalization; and (c) a novel rexinoid signaling pathway that triggers apoptosis of immature APL cells and may correspond to a default death pathway that is operative in the absence of "survival" factors. This rexinoid apoptosis is inhibited by RXR but not RAR antagonists and is distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis. Here we discuss the promise of retinoids for cancer treatment and prevention with an emphasis on the recently identified mechanisms by which they control (cancer) cell proliferation.