The cleavage fragment of retinoid X receptor-alpha ligand binding domain inhibits radiosensitization by retinoic acid.
Retinoid X receptor-alpha (RXR alpha) fragments are known to be produced in some cancer cells by proteolytic cleavage. Previous finding that ligand binding domain (LBD) fragment of RXR alpha specifically inhibits retinoic acid receptor-gamma (RAR gamma) activity led us to investigate the functional role of RXR alpha LBD fragment in radiosensitization by retinoic acid (RA). Ectopic expression of RXR alpha LBD fragment in cells that do not have a detectable endogenous RXR alpha 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 RXR alpha LBD fragment, was not radiosensitized by RA regardless of the ectopic RXR alpha LBD fragment expression. These results were paralleled with the pattern of p21 Waf1/Cip1 induction by the treatment of RA in combination with ionizing radiation (IR). Taken together, we hypothesize that the RXR alpha LBD fragment may act as a negative regulator of radiosensitizing effect of RA by restricting the RAR gamma-mediated biological response to RA.
Cho
Young-Min
YM
Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
Yang
Ae-Hee
AH
Kim
Bu-Yeon
BY
Han
Young-Hoon
YH
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008024:Ligands; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008024:Ligands; D011838:Radiation-Sensitizing Agents; D047490:Retinoid X Receptor alpha; D014212:Tretinoin