The Acute Inhibitory Effect of Iodide Excess on Sodium/Iodide Symporter Expression and Activity Involves the PI3K/Akt Signaling Pathway

Abstract

Iodide (I(-)) is an irreplaceable constituent of thyroid hormones and an important regulator of thyroid function, because high concentrations of I(-) down-regulate sodium/iodide symporter (NIS) expression and function. In thyrocytes, activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) cascade also inhibits NIS expression and function. Because I(-) excess and PI3K/Akt signaling pathway induce similar inhibitory effects on NIS expression, we aimed to study whether the PI3K/Akt cascade mediates the acute and rapid inhibitory effect of I(-) excess on NIS expression/activity. Here, we reported that the treatment of PCCl3 cells with I(-) excess increased Akt phosphorylation under normal or TSH/insulin-starving conditions. I(-) stimulated Akt phosphorylation in a PI3K-dependent manner, because the use of PI3K inhibitors (wortmannin or 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) abrogated the induction of I(-) effect. Moreover, I(-) inhibitory effect on NIS expression and function were abolished when the cells were previously treated with specific inhibitors of PI3K or Akt (Akt1/2 kinase inhibitor). Importantly, we also found that the effect of I(-) on NIS expression involved the generation of reactive oxygen species (ROS). Using the fluorogenic probes dihydroethidium and mitochondrial superoxide indicator (MitoSOX Red), we observed that I(-) excess increased ROS production in thyrocytes and determined that mitochondria were the source of anion superoxide. Furthermore, the ROS scavengers N-acetyl cysteine and 2-phenyl-1,2-benzisoselenazol-3-(2H)-one blocked the effect of I(-) on Akt phosphorylation. Overall, our data demonstrated the involvement of the PI3K/Akt signaling pathway as a novel mediator of the I(-)-induced thyroid autoregulation, linking the role of thyroid oxidative state to the Wolff-Chaikoff effect.

miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

“…PI3K is a membrane protein related to G protein-coupled receptors (42). PI3K activation triggers a series of intracellular events leading to the activation of Akt and mTOR (43)(44)(45), which thereafter induces the expression of multiple target genes that regulate cell proliferation, differentiation and other funtions (46,47). Our results revealed that the PI3K/Akt/mTOR pathway was involved in the invasion and metastasis of colon cancer cells, which was negatively regulated by miR-218.…”

Increased regucalcin gene expression extends survival in breast cancer patients: Overexpression of regucalcin suppresses the proliferation and metastatic bone activity in MDA-MB-231 human breast cancer cells in vitro

“…4B). Likewise, the proliferation of MDA-MB-231 cells (wild-type) was suppressed by culture with wortmannin (0.1 or 1 µM), an inhibitor of phosphatidylinositol 3-kinase (PI3K) (36), and PD98059 (1 or 10 µM), an extracellular signal-regulated kinase (ERK) inhibitor (37) (Fig. 4C).…”

In�vitro study on human umbilical cord mesenchymal stem cells transfected with lentivirus‑mediated hNIS‑EGFP dual reporter gene and co‑labeled with superparamagnetic iron oxide

“…However, the hNIS reporter gene lso has some deficiencies. As it is an endogenous gene, it is expressed in different degrees by several organs and tissues, such as the thyroid, gastric mucosa, mammary glands and salivary glands, which affects the monitoring of hNIS gene expression (30). In addition, in non-thyroid tissues and cells, iodine is released quickly because of a lack of thyroid specific proteins that hold iodine, therefore radioactive iodine does not accumulate (31–33).…”