Signal transducer and activator of transcription 3 and 5 regulate system Xc- and redox balance in human breast cancer cells.

Publisher: Springer Country of Publication: Netherlands NLM ID: 0364456 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-4919 (Electronic) Linking ISSN: 03008177 NLM ISO Abbreviation: Mol Cell Biochem Subsets: MEDLINE

Publication: New York : Springer
Original Publication: The Hague, Dr. W. Junk B. V. Publishers.

Breast Neoplasms/*genetics ; Breast Neoplasms/*metabolism ; STAT3 Transcription Factor/*genetics ; STAT3 Transcription Factor/*metabolism ; STAT5 Transcription Factor/*genetics ; STAT5 Transcription Factor/*metabolism ; Signal Transduction/*genetics ; Tumor Suppressor Proteins/*genetics ; Tumor Suppressor Proteins/*metabolism; Cell Line, Tumor ; Cystine/metabolism ; Female ; Glutamic Acid/metabolism ; Glutathione/metabolism ; Humans ; Oxidation-Reduction ; Promoter Regions, Genetic/genetics ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Transcriptional Activation/genetics ; Up-Regulation/genetics

System Xc- is a cystine/glutamate antiporter that contributes to the maintenance of cellular redox balance. The human xCT (SLC7A11) gene encodes the functional subunit of system Xc-. Transcription factors regulating antioxidant defense mechanisms including system Xc- are of therapeutic interest, especially given that aggressive breast cancer cells exhibit increased system Xc- function. This investigation provides evidence that xCT expression is regulated by STAT3 and/or STAT5A, functionally affecting the antiporter in human breast cancer cells. Computationally analyzing two kilobase pairs of the xCT promoter/5' flanking region identified a distal gamma-activated site (GAS) motif, with truncations significantly increasing luciferase reporter activity. Similar transcriptional increases were obtained after treating cells transiently transfected with the full-length xCT promoter construct with STAT3/5 pharmacological inhibitors. Knock-down of STAT3 or STAT5A with siRNAs produced similar results. However, GAS site mutation significantly reduced xCT transcriptional activity, suggesting that STATs may interact with other transcription factors at more proximal promoter sites. STAT3 and STAT5A were bound to the xCT promoter in MDA-MB-231 cells, and binding was disrupted by pre-treatment with STAT inhibitors. Pharmacologically suppressing STAT3/5 activation significantly increased xCT mRNA and protein levels, as well as cystine uptake, glutamate release, and total levels of intracellular glutathione. Our data suggest that STAT proteins negatively regulate basal xCT expression. Blocking STAT3/5-mediated signaling induces an adaptive, compensatory mechanism to protect breast cancer cells from stress, including reactive oxygen species, by up-regulating xCT expression and the function of system Xc-. We propose that targeting system Xc- together with STAT3/5 inhibitors may heighten therapeutic anti-cancer effects.

J Cell Physiol. 1987 Nov;133(2):330-6. (PMID: 3680392)
FEBS Lett. 2011 May 6;585(9):1363-7. (PMID: 21510944)
Gastroenterol Res Pract. 2010;2010:240365. (PMID: 21197425)
Free Radic Biol Med. 2013 Oct;63:291-303. (PMID: 23747931)
Oncogene. 2001 May 3;20(20):2499-513. (PMID: 11420660)
J Biol Chem. 1989 Nov 5;264(31):18480-4. (PMID: 2808385)
Biochem Biophys Res Commun. 2004 Dec 3;325(1):109-16. (PMID: 15522208)
J Neurochem. 2005 Mar;92 (6):1521-30. (PMID: 15748169)
J Immunol. 2007 May 15;178(10):6549-56. (PMID: 17475885)
Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1005-28. (PMID: 11076791)
Nat Rev Cancer. 2011 Feb;11(2):85-95. (PMID: 21258394)
Antioxid Redox Signal. 2013 Feb 10;18(5):522-55. (PMID: 22667998)
Blood. 1999 May 1;93(9):2928-35. (PMID: 10216087)
Cell Growth Differ. 2002 Jan;13(1):13-8. (PMID: 11801527)
Brain Res. 2010 Mar 19;1321:88-95. (PMID: 20102705)
Nat Rev Cancer. 2003 Nov;3(11):859-68. (PMID: 14668816)
Cell Signal. 2008 Feb;20(2):390-9. (PMID: 18054200)
Pflugers Arch. 2004 Feb;447(5):532-42. (PMID: 14770310)
Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1339-49. (PMID: 16910781)
Mol Cell Biol. 2007 Sep;27(18):6300-8. (PMID: 17636030)
Mol Endocrinol. 1994 Dec;8(12):1742-9. (PMID: 7708061)
J Invest Dermatol. 2014 Jun;134(6):1570-1578. (PMID: 24441101)
Trends Endocrinol Metab. 2009 Nov;20(9):436-43. (PMID: 19800252)
J Hepatol. 2006 Aug;45(2):271-9. (PMID: 16595158)
J Biol Chem. 2001 Mar 30;276(13):10407-12. (PMID: 11136724)
Immunity. 1995 Jun;2(6):689-97. (PMID: 7796300)
Mol Cell Biol. 2003 Dec;23(24):8934-45. (PMID: 14645506)
J Biol Chem. 2005 Nov 11;280(45):37423-9. (PMID: 16144837)
Cancer Res. 2010 Apr 15;70(8):3391-401. (PMID: 20388777)
Cytokine Growth Factor Rev. 2010 Feb;21(1):11-9. (PMID: 20018552)
Antioxid Redox Signal. 2008 Aug;10(8):1343-74. (PMID: 18522489)
ACS Med Chem Lett. 2013 Sep 08;4(11):1102-7. (PMID: 24900612)
JAKSTAT. 2013 Oct 1;2(4):e25764. (PMID: 24416651)
J Pharmacol Exp Ther. 2010 Mar;332(3):949-58. (PMID: 20007406)
J Biol Chem. 2002 Nov 22;277(47):44765-71. (PMID: 12235164)
Oncogene. 2007 Sep 20;26(43):6341-8. (PMID: 17438530)
J Clin Immunol. 2002 Jul;22(4):185-94. (PMID: 12148593)
J Biol Chem. 2013 May 24;288(21):14815-23. (PMID: 23592778)
Biochem Biophys Res Commun. 2014 Jul 18;450(1):135-41. (PMID: 24866234)
Cancer Res. 2014 Apr 15;74(8):2295-305. (PMID: 24686172)
Am J Physiol. 1998 Dec;275(6 Pt 1):C1640-52. (PMID: 9843726)
Cancer Res. 2005 Aug 15;65(16):7446-54. (PMID: 16103098)
Inflamm Bowel Dis. 2011 May;17(5):1177-88. (PMID: 20824812)
Invest Ophthalmol Vis Sci. 2008 Jan;49(1):310-9. (PMID: 18172108)
Mol Cell Biol. 2014 Oct;34(20):3800-16. (PMID: 25092871)
Cell Signal. 1997 Jan;9(1):85-9. (PMID: 9067635)
Biochem J. 1995 Sep 1;310 ( Pt 2):547-51. (PMID: 7654193)
Nature. 2007 Jun 21;447(7147):972-8. (PMID: 17538624)
Oxid Med Cell Longev. 2013;2013:737591. (PMID: 23710289)
Drug Metab Rev. 2006;38(4):769-89. (PMID: 17145701)
Cancers (Basel). 2014 Apr 16;6(2):926-57. (PMID: 24743778)
Mol Cell Biol. 2014 Sep 15;34(18):3421-34. (PMID: 25002527)
Cell Signal. 2006 Feb;18(2):174-82. (PMID: 15982852)
Carcinogenesis. 2013 Mar;34(3):620-6. (PMID: 23161574)
Cancer Res. 2007 Feb 15;67(4):1472-86. (PMID: 17308085)
Glia. 2010 Nov 15;58(15):1806-15. (PMID: 20645408)
Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3041-5. (PMID: 7708771)
BMC Cancer. 2014 Jun 09;14:415. (PMID: 24913037)
Neuropharmacology. 2012 Feb;62(2):901-6. (PMID: 21967732)
Nat Rev Drug Discov. 2009 Jul;8(7):579-91. (PMID: 19478820)
J Biol Chem. 1984 Feb 25;259(4):2435-40. (PMID: 6142042)
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9926-30. (PMID: 7937919)
Carcinogenesis. 2004 Nov;25(11):2033-44. (PMID: 15180945)
Genes Dev. 1995 Apr 15;9(8):984-94. (PMID: 7774815)
Cerebellum. 2007;6(4):308-14. (PMID: 17853088)
Neurosci Lett. 2000 Mar 3;281(1):61-4. (PMID: 10686416)
Oncogene. 2009 Jan 29;28(4):599-609. (PMID: 19015640)
Cancer Cell. 2011 Mar 8;19(3):387-400. (PMID: 21397861)
Curr Pharm Des. 2008;14(11):1113-23. (PMID: 18473858)
Breast Cancer. 2002;9(4):312-8. (PMID: 12459712)
J Cell Physiol. 2008 Jun;215(3):593-602. (PMID: 18181196)

Canada Canadian Institutes of Health Research

0 (RNA, Messenger)
0 (RNA, Small Interfering)
0 (Reactive Oxygen Species)
0 (STAT3 Transcription Factor)
0 (STAT3 protein, human)
0 (STAT5 Transcription Factor)
0 (STAT5A protein, human)
0 (Tumor Suppressor Proteins)
3KX376GY7L (Glutamic Acid)
48TCX9A1VT (Cystine)
GAN16C9B8O (Glutathione)

Date Created: 20150422 Date Completed: 20160216 Latest Revision: 20181113

20250114

10.1007/s11010-015-2412-4

25896132