THRΒ radiosensitizes cells and potentiates cellular senescence

Abstract

Background.
Thyroid hormone receptors (THR) broadly regulate cell differentiation and metabolism acting as ligand-inducible transcription factors. Given a large variety of genes regulated by THRs and multiplicity of cellular processes potentially influenced by THRs, we addressed the role of THRΒ (thyroid hormone receptor beta) in cell radiosensitivity.
Material and Methods.
Wild-type and mutant THRΒ were overexpressed in several cell lines using an adenovirus-mediated gene delivery and their effects were examined after cell exposure to Γ-rays.
Results.
Wild-type THRΒ decreased clonogenic survival of the cell lines with low levels of endogenous THRΒ, retarded their growth and synergized with radiation in decreasing proliferative potential and promoting cellular senescence. These changes were accompanied by the accumulation of p21 and p16 inhibitors of cyclin-dependent kinases and by the decrease of Rb (retinoblastoma protein) phosphorylation. Mutant THRΒ produced a radioprotective effect, attenuated radiation-induced growth inhibition and cellular senescence.
Conclusions.
The results demonstrate that THRΒ is one of the factors that modulate cell radiosensitivity. This newly recognized property of THRΒ may be used for identification of the molecular mechanisms underlying cell radiosensitization and stress-induced senescence.