title: Cyclohexylmethyl Flavonoids Suppress Propagation of Breast Cancer Stem Cells via Downregulation of NANOG.
abstract: Breast cancer stem cells (CSCs) are highly tumorigenic and possess the capacity to self-renew. Recent studies indicated that pluripotent gene NANOG involves in regulating self-renewal of breast CSCs, and expression of NANOG is correlated with aggressiveness of poorly differentiated breast cancer. We initially confirmed that breast cancer MCF-7 cells expressed NANOG, and overexpression of NANOG enhanced the tumorigenicity of MCF-7 cells and promoted the self-renewal expansion of CD24(-/low)CD44(+) CSC subpopulation. In contrast, knockdown of NANOG significantly affected the growth of breast CSCs. Utilizing flow cytometry, we identified five cyclohexylmethyl flavonoids that can inhibit propagation of NANOG-positive cells in both breast cancer MCF-7 and MDA-MB231 cells. Among these flavonoids, ugonins J and K were found to be able to induce apoptosis in non-CSC populations and to reduce self-renewal growth of CD24(-/low)CD44(+) CSC population. Treatment with ugonin J significantly reduced the tumorigenicity of MCF-7 cells and efficiently suppressed formation of mammospheres. This suppression was possibly due to p53 activation and NANOG reduction as either addition of p53 inhibitor or overexpression of NANOG can counteract the suppressive effect of ugonin J. We therefore conclude that cyclohexylmethyl flavonoids can possibly be utilized to suppress the propagation of breast CSCs via reduction of NANOG.
authors: Stem Cell Program, Genomics Research Center, Academia Sinica, Nangang, Taipei 115, Taiwan ; Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 402, Taiwan.
authors: Wen-Ying
authors: WY
authors: Liao
authors: Chih-Chuang
authors: CC
authors: Liaw
authors: Yuan-Chao
authors: YC
authors: Huang
authors: Hsin-Ying
authors: HY
authors: Han
authors: Hung-Wei
authors: HW
authors: Hsu
authors: Shiaw-Min
authors: SM
authors: Hwang
authors: Sheng-Chu
authors: SC
authors: Kuo
authors: Chia-Ning
authors: CN
authors: Shen
references: Stem Cells. 2009 May;27(5):993-1005
references: 19415763
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references: 12629218
references: J Nat Prod. 2007 Feb;70(2):147-53
references: 17315955
references: Int J Dev Biol. 2010;54(11-12):1743-54
references: 21136380
references: J Clin Invest. 2007 Dec;117(12):3988-4002
references: 18060036
references: J Mol Signal. 2010 Aug 18;5:14
references: 20718984
references: J Ethnopharmacol. 2004 May;92(1):61-6
references: 15099849
references: J Natl Cancer Inst. 2010 May 19;102(10):680-91
references: 20427433
references: Nat Cell Biol. 2005 Feb;7(2):165-71
references: 15619621
references: Expert Opin Ther Targets. 2012 Dec;16(12):1161-74
references: 22998602
references: Oncogene. 2011 Sep 8;30(36):3833-45
references: 21499299
references: Nature. 2004 Nov 18;432(7015):324-31
references: 15549094
references: J Natl Cancer Inst. 2008 May 7;100(9):672-9
references: 18445819
references: Planta Med. 2010 Mar;76(5):447-53
references: 19844863
references: J Transl Med. 2012 Sep 19;10 Suppl 1:S12
references: 23046537
references: Cancer Res. 2005 Jul 15;65(14):6207-19
references: 16024622
references: Nat Cell Biol. 2000 Sep;2(9):563-8
references: 10980695
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3547-9
references: 12657737
references: J Biol Chem. 2008 Jun 20;283(25):17635-51
references: 18441325
references: Am J Pathol. 2011 Jul;179(1):2-11
references: 21640330
references: Cell Cycle. 2012 Jul 15;11(14):2583-4
references: 22751434
references: FEBS J. 2006 Apr;273(8):1723-30
references: 16623708
references: Semin Oncol. 2002 Dec;29(6):563-74
references: 12516039
references: J Clin Oncol. 2010 Sep 1;28(25):4006-12
references: 20498387
references: Nat Genet. 2008 May;40(5):499-507
references: 18443585
references: J Nat Prod. 2009 Jul;72(7):1273-8
references: 19583252
references: PLoS One. 2008;3(12):e4023
references: 19107196
references: N Engl J Med. 2007 Jan 18;356(3):217-26
references: 17229949
references: Carcinogenesis. 2011 May;32(5):650-8
references: 21310941
references: J Clin Oncol. 2008 Jun 10;26(17):2846-53
references: 18539963
references: Science. 2007 Dec 21;318(5858):1917-20
references: 18029452
references: Biochem Biophys Res Commun. 2007 Feb 16;353(3):699-705
references: 17196549
references: Cancer Lett. 2012 Aug 1;321(1):80-8
references: 22381696
references: Cell. 2003 May 30;113(5):643-55
references: 12787505