Casein Kinase 1α Interacts with Retinoid X Receptor and Interferes with Agonist-induced Apoptosis

Agonists of retinoid X receptors (RXRs), which include the natural 9- cis -retinoic acid and synthetic analogs, are potent inducers of growth arrest and apoptosis in some cancer cells. As such, they are being used in clinical trials for the treatment and prevention of solid tumors and are used to treat cutaneous T cell lymphoma. However, the molecular mechanisms that underlie the anti-cancer effects of RXR agonists remain unclear. Here, we show that a novel pro-apoptotic pathway that is induced by RXR agonist is negatively regulated by casein kinase 1α (CK1α). CK1α associates with RXR in an agonist-dependent manner and phosphorylates RXR. The ability of an RXR agonist to recruit CK1α to a complex with RXR in cells correlates inversely with its ability to inhibit growth. Remarkably, depletion of CK1α in resistant cells renders them susceptible to RXR agonist-induced growth inhibition and apoptosis. Our study shows that CK1α can promote cell survival by interfering with RXR agonist-induced apoptosis. Inhibition of CK1α may enhance the anti-cancer effects of RXR agonists.