Solomon, C., White, J. H., Rhim, J. S. and Kremer R. Vitamin D Resistance in RAS-Transformed Keratinocytes: Mechanism and Reversal Strategies.

Human retinoid X receptor α (hRXRα) plays a critical role in DNA binding and transcriptional activity through its heterodimeric association with several members of the nuclear receptor superfamily, including the vitamin D receptor (VDR). Several cancer cell lines derived from different tissues have been shown to be resistant to the growth-inhibitory action of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the biologically active metabolite of vitamin D₃. Here we show that in RAS-transformed keratinocytes, Ser260 of hRXRα is phosphorylated through the RAS-RAF-MAP kinase cascade. This phosphorylation event results in the inhibition of vitamin D signaling via VDR/hRXRα heterodimers. Strategies to reverse this resistance include the use of the MAP kinase inhibitor, PD098059, and a non-phosphorylatable hRXRα mutant, Ala260, which completely abolishes RXR phosphorylation and restores the function of both 1,25(OH)₂D₃ and a specific RXR ligand, LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl)ethenyl]-benzoic acid). In addition, we show that a vitamin D analog with low calcemic activity (EB1089) is more potent than 1,25(OH)₂D₃ in inhibiting cancer cell growth in this system. Targeted therapy with selective analogs such as EB1089, in combination with the inhibition of phosphorylation of the RXR, could play a critical role in the development of strategies for cancer treatment.