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.