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

J Clin Endocrinol Metab. 2008 May;93(5):1884-92. doi: 10.1210/jc.2007-1627. Epub 2008 Mar 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromones / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Female
  • Humans
  • Insulin-Like Growth Factor I / physiology*
  • MAP Kinase Signaling System
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase C / physiology
  • Signal Transduction / physiology*
  • Symporters / genetics*
  • Tretinoin / pharmacology*
  • Tyrphostins / pharmacology
  • p38 Mitogen-Activated Protein Kinases / physiology*

Substances

  • Chromones
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Symporters
  • Tyrphostins
  • tyrphostin AG 1024
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • sodium-iodide symporter
  • Tretinoin
  • Insulin-Like Growth Factor I
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • p38 Mitogen-Activated Protein Kinases