Involvement of mTOR and Regulation by AMPK in Early Iodine Deficiency-Induced Thyroid Microvascular Activation

Abstract

Iodine deficiency (ID) induces TSH-independent microvascular activation in the thyroid via the reactive oxygen species/nitric oxide-hypoxia-inducible factor-1α/vascular endothelial growth factor (VEGF) pathway. We hypothesized the additional involvement of mammalian target of rapamycin (mTOR) as a positive regulator of this pathway and AMP-activated protein kinase (AMPK) as a negative feedback regulator to explain the transient nature of ID-induced microvascular changes under nonmalignant conditions. mTOR and AMPK involvement was investigated using an in vitro model (human thyrocytes in primary cultures) and 2 murine models of goitrogenesis (normal NMRI and RET-PTC mice [a papillary thyroid cancer model]). In NMRI mice, ID had no effect on the phosphorylation of ribosomal S6 kinase (p70S6K), a downstream target of mTOR. However, rapamycin inhibited ID-induced thyroid blood flow and VEGF protein expression. In the RET-PTC model, ID strongly increased the phosphorylation of p70S6K, whereas rapamycin completely inhibited the ID-induced increase in p70S6K phosphorylation, thyroid blood flow, and VEGF-A expression. In vitro, although ID increased p70S6K phosphorylation, the ID-stimulated hypoxia-inducible factor/VEGF pathway was inhibited by rapamycin. Activation of AMPK by metformin inhibited ID effects both in vivo and in vitro. In AMPK-α1 knockout mice, the ID-induced increase in thyroid blood flow and VEGF-A protein expression persisted throughout the treatment, whereas both parameters returned to control values in wild-type mice after 4 days of ID. In conclusion, mTOR is required for early ID-induced thyroid microvascular activation. AMPK negatively regulates this pathway, which may account for the transient nature of ID-induced TSH-independent vascular effects under benign conditions.

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

“…Thyroidstimulating hormone (TSH), produced by thyrotrophic cells in the pituitary gland, stimulates TH biosynthesis and secretion, while the production of TSH is regulated by the hypothalamic TSHreleasing hormone and modulated by TH via a negative feedback loop. Interaction of TSH with the TSH receptor (TSHR), a G proteincoupled receptor (Gα q /Gα 11 ), leads to activation of several kinase signaling cascades, including PKA, PKC, AMPK, and the PI3K/ mTOR complex 1 (mTORC1) pathways (2)(3)(4)(5)(6)(7)(8). Through these pathways, TSH regulates the expression of genes that are associated with thyroid gland development and TH biosynthesis and secretion, including thyroid peroxidase (TPO), and the Na + /I -symporter (NIS; SLC5A5) and iodide transporter pendrin (PDS, also referred to as SLC26A4) (7,9,10).…”

“…Through these pathways, TSH regulates the expression of genes that are associated with thyroid gland development and TH biosynthesis and secretion, including thyroid peroxidase (TPO), and the Na + /I -symporter (NIS; SLC5A5) and iodide transporter pendrin (PDS, also referred to as SLC26A4) (7,9,10). Prolonged TSH stimulation causes proliferation of thyroid follicular cells, leading to enlargement of the thyroid gland (goiter) (6,8,11).…”

The roles and role-players in thyroid cancer angiogenesis

“…The results of that study indicate that induction of angiogenesis in cancer cells via alternative and likely less controlled pathways could result in uncontrolled growth [184]. More recently, Craps, et al studied the involvement of mammalian target of rapamycin (mTOR) as a positive regulator and AMP-activated protein kinase (AMPK) as a negative feedback regulator of ROS/HIF-1/VEGF pathway to describe alterations of microvasculature in iodine-deficient models, including human thyrocytes and two murine models of goitrogenesis: normal NMRI and RET-PTC mice (a PTC model) [185]. Iodine deficiency (ID) significantly increased the phosphorylation of ribosomal S6 kinase (p70S6K), a downstream target of mTOR, whereas rapamycin completely inhibited the IDinduced increase in p70S6K phosphorylation, thyroid blood flow, and VEGF-A expression in the RET-PTC and in-vitro models.…”

“…However, these effects have not shown in NMRI model. The authors concluded that mTOR is needed for early ID-induced thyroid microvascular activation, however, AMPK negatively regulates this pathway [185]. On the other hand, excess iodine can have suppressing effects on thyroid dependent angiogenesis.…”

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

“…Thyroidstimulating hormone (TSH), produced by thyrotrophic cells in the pituitary gland, stimulates TH biosynthesis and secretion, while the production of TSH is regulated by the hypothalamic TSHreleasing hormone and modulated by TH via a negative feedback loop. Interaction of TSH with the TSH receptor (TSHR), a G proteincoupled receptor (Gα q /Gα 11 ), leads to activation of several kinase signaling cascades, including PKA, PKC, AMPK, and the PI3K/ mTOR complex 1 (mTORC1) pathways (2)(3)(4)(5)(6)(7)(8). Through these pathways, TSH regulates the expression of genes that are associated with thyroid gland development and TH biosynthesis and secretion, including thyroid peroxidase (TPO), and the Na + /Isymporter (NIS; SLC5A5) and iodide transporter pendrin (PDS, also referred to as SLC26A4) (7,9,10).…”