Evidence that the inhibitory effects of iodide on thyroid cell proliferation are due to arrest of the cell cycle at G0G1 and G2M phases.

Abstract

The thyroid gland is unique in its ability to respond to ambient levels of iodine to autoregulate thyroid function and, possibly, thyroid cell proliferation. Although the inhibitory effects of iodide on thyroid cell proliferation have been previously reported, the exact mechanism and site of action of iodide on cellular proliferation events are poorly understood. Our initial experiments established the optimal cell plating density and timing to achieve exponential cell growth of FRTL5 thyroid cells, and subsequent studies using flow cytometric DNA analysis established the normal cell cycle kinetics of FRTL5 thyroid cell proliferation. FRTL5 cells were then exposed to graded concentrations of sodium iodide to establish whether the inhibitory effects of iodide are mediated through specific cell cycle events. We observed that increasing concentrations of iodide inhibited FRTL5 thyroid cell proliferation. Analysis of the cell cycle revealed two specific effects of iodide on cell cycle kinetics. The first was an arrest of cells in G0G1, evidenced by an accumulation of cells in this phase and a concomitant reduction in the percentage of cells in the S-phase. The second was an arrest of cells in the G2M phase of the cycle. G0G1 and G2M arrest occurred within 24 h and then reached a plateau. Iodide exposure did not increase the number of cells undergoing necrosis. The addition of methimazole at two concentrations (0.2 and 2 mM) to cells exposed to 100 mM NaI prevented the accumulation of cells in G2M, but did not abolish the accumulation of cells in G0G1 or the reduction in cell number. These results indicate that the inhibitory effects of iodide on FRTL5 thyroid cell proliferation are mediated by its action at two critical regulating points of the cell cycle, G0G1 and G2M. It appears that organified iodine may mediate the cell cycle arrest in the G2M phase, whereas inorganic iodide may be responsible for the inhibitory effects at G0G1.

Signaling pathways involved in the antiproliferative effect of molecular iodine in normal and tumoral breast cells: evidence that 6-iodolactone mediates apoptotic effects

“…These data agree with previous results showing that, in thyroid FRTL-5 cells, iodide induces cell cycle arrest in both G1 and G2/M phases (Smerdely et al 1993). The p53 protein can regulate the G 1 or G 2 /M transition by inducing p21, an inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes (Roninson 2002).…”

Biological activity of activating thyrotrophin receptor mutants: modulation by iodide

“…In contrast the inhibition of proliferation induced by NaI is associated with more cells in the G2 and post-G2 'endoreduplication' populations. These data suggest that cell-cycle blockade (at G2/M) and endocycle escape contribute to the mechanism of inhibition, and are in agreement with studies from Smerdely et al (1993), who demonstrated significant reduction in TSH-induced proliferation by 100 mM NaI. This was attributable to accumulation of the cells both in G0/G1 and G2/M.…”

“…Iodide inhibits thyroid adenylate cyclase producing a reduction in TSH-or forskolin-stimulated cAMP production in several species (Van Sande et al 1985). Although this, in itself, would have a negative impact on thyrocyte growth, it is unrelated to the G2/M arrest in the cell cycle of FRTL-5 induced by iodide (Smerdely et al 1993(Smerdely et al , 1995. Iodide has also been demonstrated to induce apoptosis in a thyroid cell line via a p53 independent mechanism (Vitale et al 2000).…”

Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat

“…The irregular shaped nuclei with chromatin aggregates observed in the thyrocytes of the AMD groups have also been observed in other tissues such as rat hepatocytes exposed to AMD (20). AMD may induce apoptosis either directly, or indirectly by virtue of the high levels of iodide in the drug, as shown by Smerdely et al (21). In our experiments, apoptosis was not evident at the level of iodide used here, suggesting that the effects observed with AMD are not primarily related to the iodine content of the drug alone (22,23).…”