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1 January 2001 Vitamin D Resistance in RAS-Transformed Keratinocytes: Mechanism and Reversal Strategies
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Abstract

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.

Cynthia Solomon, John H. White, Johng S. Rhim, and Richard Kremer "Vitamin D Resistance in RAS-Transformed Keratinocytes: Mechanism and Reversal Strategies," Radiation Research 155(1), (1 January 2001). https://doi.org/10.1667/0033-7587(2001)155[0156:VDRIRT]2.0.CO;2
Received: 16 November 1999; Accepted: 1 August 2000; Published: 1 January 2001
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