Abstract
Thyroid hormone receptors (THRs) are transcription factors that regulate the expression of a variety of genes affecting cell growth and differentiation. Somatic mutations in the THR genes were found in human malignancies suggestive of their implication in carcinogenesis. In view of a broad range of intracellular processes dependent on the functional THRs, we set out to clarify the influence of THRB1 on cell radiosensitivity.
Using an adenoviral vector, wild type (wt) and mutant (mut) THRB1 were overexpressed in TPC1, NPA, FRO, ARO , MCF-7 and COS-7 . Infected cells were irradiated with 0-7 Gy of gamma-rays and subjected to a colony formation assay.
No significant changes in clonogenic survival were observed in TPC1, NPA and FRO cells (all display a high level of endogenous THRB1 protein). By contrast, in ARO, MCF-7 and COS-7 cells (with a low to absent endogenous THRB1), wtTHRB1 decreases and mutTHRB1 increased clonogenicity. Western blotting demonstrated that in the presence of wtTHRB1, ARO cells had elevated levels of cleaved PARP and markedly diminished levels of cyclin D1 as compared to mutTHRB1-infected and/or irradiated cells. In MCF-7, mutTHRB1 overexpression resulted in a strong upregulation of pospho-AKT. Thus, THRB1 can possibly mediate radiation effects by influencing apoptotic, cell cycle progression and survival programs. Dominance of each of signaling cascades appears to be cell type-specific. In conclusion, the net effect of wtTHRB1 is radiosensibilizing but that of mutTHRB1 – radioprotective.
