Retinoid X receptor-α (RXRα) fragments are known to be produced in some cancer cells by proteolytic cleavage. Previous finding that ligand binding domain (LBD) fragment of RXRα specifically inhibits retinoic acid receptor-γ (RARγ) activity led us to investigate the functional role of RXRα LBD fragment in radiosensitization by retinoic acid (RA). Ectopic expression of RXRα LBD fragment in cells that do not have a detectable endogenous RXRα LBD fragment, blocked synergistic radiosensitizing action of RA, as determined by growth inhibition, cell death and colony formation assays. However, H460 cell, which has an endogenous RXRα LBD fragment, was not radiosensitized by RA regardless of the ectopic RXRα LBD fragment expression. These results were paralleled with the pattern of p21Waf1/Cip1 induction by the treatment of RA in combination with ionizing radiation (IR). Taken together, we hypothesize that the RXRα LBD fragment may act as a negative regulator of radiosensitizing effect of RA by restricting the RARγ-mediated biological response to RA.

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