title: Regulation of sodium iodide symporter gene expression by Rac1/p38β mitogen-activated protein kinase signaling pathway in MCF-7 breast cancer cells.
abstract: Activation of p38 MAPK is a key pathway for cell proliferation and differentiation in breast cancer and thyroid cells. The sodium/iodide symporter (NIS) concentrates iodide in the thyroid and lactating breast. All-trans-retinoic acid (tRA) markedly induces NIS activity in some breast cancer cell lines and promotes uptake of β-emitting radioiodide (131)I sufficient for targeted cytotoxicity. To identify a signal transduction pathway that selectively stimulates NIS expression, we investigated regulation by the Rac1-p38 signaling pathway in MCF-7 breast cancer cells and compared it with regulation in FRTL-5 rat thyroid cells. Loss of function experiments with pharmacologic inhibitors and small interfering RNA, as well as RT-PCR analysis of p38 isoforms, demonstrated the requirement of Rac1, MAPK kinase 3B, and p38β for the full expression of NIS in MCF-7 cells. In contrast, p38α was critical for NIS expression in FRTL-5 cells. Treatment with tRA or overexpression of Rac1 induced the phosphorylation of p38 isoforms, including p38β. A dominant negative mutant of Rac1 abolished tRA-induced phosphorylation in MCF-7 cells. Overexpression of p38β or Rac1 significantly enhanced (1.9- and 3.9-fold, respectively), the tRA-stimulated NIS expression in MCF-7 cells. This study demonstrates differential regulation of NIS by distinct p38 isoforms in breast cancer cells and thyroid cells. Targeting isoform-selective activation of p38 may enhance NIS induction, resulting in higher efficacy of (131)I concentration and treatment of breast cancer.
authors.affiliation: Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA. tkogai@ucla.edu
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kogai
authors.forename: Yan-Yun
authors.initials: YY
authors.lastname: Liu
authors.forename: Kaizeen
authors.initials: K
authors.lastname: Mody
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Shamsian
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Brent
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007455:Iodine / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051381:Rats; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099209:Sodium-Iodide Symporters
chemical_list: D000970:Antineoplastic Agents; D007455:Iodine; D007527:Isoenzymes; D009363:Neoplasm Proteins; D027981:Symporters; D014212:Tretinoin; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D000099209:Sodium-Iodide Symporters; C107953:RAC1 protein, human; C499134:Rac1 protein, rat