Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells.

TSH stimulation of sodium iodide symporter (NIS) expression in thyroid cancer promotes radioiodine uptake and is required to deliver an effective treatment dose. Activation of the insulin/phosphoinositide-3-kinase (PI3K) signaling pathway in TSH-stimulated thyroid cells reduces NIS expression at the transcriptional level. We, therefore, investigated the effects of PI3K pathway inhibition on iodide uptake and NIS expression in rat thyroid cell lines and human papillary thyroid cancer cells. A PI3K inhibitor, LY294002, significantly enhanced iodide uptake in two rat thyroid cell lines, FRTL-5 and PCCL3. The induction of Nis mRNA by LY294002 occurred 6 h after treatment, and was abolished by a translation inhibitor, cycloheximide. Expression of the transcription factor, Pax8, which stimulates NIS expression, was significantly increased in PCCL3 cells after LY294002 treatment. Removal of insulin abrogated the stimulatory effects of LY294002 on NIS mRNA and protein expression, but not on iodide uptake. These findings suggest that PI3K pathway inhibition results in post-translational stimulation of NIS. Inhibition of the PI3K pathway also significantly increased iodide uptake ( approximately 3.5-fold) in BHP 2-7 papillary thyroid cancer cells (Ret/PTC1 positive), engineered to constitutively express NIS. Pharmacological inhibition of Akt, a factor stimulated by the PI3K pathway, increased exogenous NIS expression in BHP 2-7 as was seen with LY294002, but not increase the endogenous NIS expression in FRTL-5 cells. PI3K pathway inhibition increases functional NIS expression in rat thyroid cells and some papillary thyroid cancer cells by several mechanisms. PI3K inhibitors have the potential to increase radioiodide accumulation in some differentiated thyroid cancer.

Cinacalcet for the treatment of primary hyperparathyroidism.

Primary hyperparathyroidism (HPT) is the leading cause of hypercalcemia in the outpatient setting, and it is treated primarily by parathyroidectomy. There are few nonsurgical treatment options for patients who do not wish to have surgery, who have failed surgery, or who have contraindications to surgery. Cinacalcet increases the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing serum calcium levels. We conducted a retrospective chart review from 2004 to 2006 to investigate the efficacy of cinacalcet in reducing serum total calcium, ionized calcium, and parathyroid hormone (PTH) in patients with primary HPT. Patients were started on cinacalcet if they met at least one indication for parathyroidectomy, which includes T score less than -2.5 standard deviations from the mean, serum calcium 1 mg/dL above the upper limit of normal, 24-hour urine calcium above 400 mg/dL, age less than 50 years, or a creatinine clearance that is 30% below age- and sex-matched controls. The primary outcome was normalization of serum calcium. A total of 18 patients with primary HPT were started on cinacalcet: 16 men and 2 women with a mean age of 70 years. Mean baseline serum calcium was 10.60 +/- .53 mg/dL; ionized serum calcium, 1.45 +/- .07 mmol/L; and serum PTH, 141 +/- 78 pg/mL. After treatment with cinacalcet, the mean serum calcium decreased to 9.46 +/- .34 mg/dL, ionized calcium decreased to 1.26 +/- .06 mmol/L, and PTH decreased to 108 +/- 64.5 pg/mL. Ninety-four percent of the patients on cinacalcet had normal total serum calcium, 81% had normal serum ionized calcium, whereas only 25% had a normal serum PTH level. Cinacalcet normalizes serum calcium in most patients while only modestly reducing serum PTH levels.

Retinoic acid stimulation of the sodium/iodide symporter in MCF-7 breast cancer cells is mediated by the insulin growth factor-I/phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase signaling pathways.

CONTEXT: All-trans retinoic acid (tRA) induces differentiation in MCF-7 breast cancer cells, stimulates sodium/iodide symporter (NIS) gene expression, and inhibits cell proliferation. Radioiodine administration after systemic tRA treatment has been proposed as an approach to image and treat some differentiated breast cancer. OBJECTIVE: The objective of this work was to study the relative role of genomic and nongenomic pathways in tRA stimulation of NIS expression in MCF-7 cells. DESIGN: We inspected the human NIS gene locus for retinoic acid-responsive elements and tested them for function. The effects of signal transduction pathway inhibitors were also tested in tRA-treated MCF-7 cells and TSH-stimulated FRTL-5 rat thyroid cells, followed by iodide uptake assay, quantitative RT-PCR of NIS, and cell cycle phase analysis. RESULTS: Multiple retinoic acid response elements around the NIS locus were identified by sequence inspection, but none of them was a functional tRA-induced element in MCF-7 cells. Inhibitors of the IGF-I receptor, Janus kinase, and phosphatidylinositol 3-kinase (PI3K), significantly reduced NIS mRNA expression and iodide uptake in tRA-stimulated MCF-7 cells but not FRTL-5 cells. An inhibitor of p38 MAPK significantly reduced iodide uptake in both tRA-stimulated MCF-7 cells and TSH-stimulated FRTL-5 cells. IGF-I and PI3K inhibitors did not significantly reduce the basal NIS mRNA expression in MCF-7 cells. Despite the chronic inhibitory effects on cell proliferation, tRA did not reduce the S-phase distribution of MCF-7 cells during the period of NIS induction. CONCLUSION: The IGF-I receptor/PI3K pathway mediates tRA-stimulated NIS expression in MCF-7 but not FRTL-5 thyroid cells.