Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells.
3,3'-Diindolylmethane (DIM) is a known anti-tumor agent against breast and other cancers; however, its exact mechanism of action remains unclear. The urokinase plasminogen activator (uPA) and its receptor (uPAR) system are involved in the degradation of basement membrane and extracellular matrix, leading to tumor cell invasion and metastasis. Since uPA-uPAR system is highly activated in aggressive breast cancer, we hypothesized that the biological activity of B-DIM could be mediated via inactivation of uPA-uPAR system. We found that B-DIM treatment as well as silencing of uPA-uPAR led to the inhibition of cell growth and motility of MDA-MB-231 cells, which was in part due to inhibition of VEGF and MMP-9. Moreover, silencing of uPA-uPAR led to decreased sensitivity of these cells to B-DIM indicating an important role of uPA-uPAR in B-DIM-mediated inhibition of cell growth and migration. We also found similar effects of B-DIM on MCF-7, cells expressing low levels of uPA-uPAR, which was due to direct down-regulation of MMP-9 and VEGF, independent of uPA-uPAR system. Interestingly, over-expression of uPA-uPAR in MCF-7 cells attenuated the inhibitory effects of B-DIM. Our results, therefore, suggest that B-DIM down-regulates uPA-uPAR in aggressive breast cancers but in the absence of uPA-uPAR, B-DIM can directly inhibit VEGF and MMP-9 leading to the inhibition of cell growth and migration of breast cancer cells.
Ahmad
Aamir
A
Department of Pathology, Barbara Ann Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Kong
Dejuan
D
Wang
Zhiwei
Z
Sarkar
Sanila H
SH
Banerjee
Sanjeev
S
Sarkar
Fazlul H
FH
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007211:Indoles; D055293:Receptors, Urokinase Plasminogen Activator; D042461:Vascular Endothelial Growth Factor A; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C016392:3,3'-diindolylmethane
Int J Biol Markers. 2001 Jan-Mar;16(1):62-8
11288958
J Cell Biochem. 2009 Jun 1;107(3):516-27
19330806
Mol Cancer Ther. 2008 Jun;7(6):1708-19
18566242
Histol Histopathol. 2009 Jul;24(7):869-77
19475533
J Cell Biochem. 2008 Dec 15;105(6):1461-71
18980240
Cancer Causes Control. 1991 Sep;2(5):325-57
1834240
J Cell Biol. 1998 Jan 12;140(1):233-45
9425170
Carcinogenesis. 2002 Aug;23(8):1297-305
12151347
Pharmacol Res. 2007 Mar;55(3):224-36
17317210
J Nutr. 2007 Jan;137(1):31-6
17182797
Stem Cells. 2008 Jun;26(6):1406-13
18403751
Oncogene. 2005 Mar 31;24(14):2343-53
15735741
Cancer Treat Rev. 2008 Apr;34(2):122-36
18162327
Cancer Prev Res (Phila). 2009 Mar;2(3):251-6
19223575
Prostate. 2004 Oct 1;61(2):153-60
15305338
CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
19474385
Br J Cancer. 2004 Oct 4;91(7):1358-63
15328526
Mol Cancer Ther. 2006 Nov;5(11):2747-56
17121921
J Biol Chem. 1998 Dec 11;273(50):33267-72
9837898
Int J Cancer. 2007 Nov 15;121(10):2307-16
17657740
Drug Metab Dispos. 2004 Jun;32(6):632-8
15155555
Cancer Res. 2007 Apr 1;67(7):3310-9
17409440
Nat Rev Cancer. 2003 Jul;3(7):489-501
12835669
Carcinogenesis. 2005 Apr;26(4):771-8
15661811
Cancer Lett. 2008 Jun 28;265(1):113-23
18378071
J Nutr. 2009 Jan;139(1):26-32
19056653
J Biol Chem. 2007 Jul 20;282(29):21542-50
17522055
Med Res Rev. 2001 Mar;21(2):146-70
11223863
In Vivo. 2008 Jul-Aug;22(4):441-5
18712169
Mol Cancer Ther. 2008 Feb;7(2):341-9
18281517
Int J Oncol. 2006 Apr;28(4):831-9
16525631
Cancer Res. 2005 Jan 1;65(1):364-71
15665315
Cancer Lett. 2007 Feb 8;246(1-2):262-7
17319000
J Nutr. 2001 Nov;131(11 Suppl):3078S-81S
11694651
Cancer Res. 2006 May 1;66(9):4880-7
16651444
Cancer Res. 2006 May 1;66(9):4952-60
16651453
Cancer Metastasis Rev. 2001;20(3-4):287-96
12085967
Cancer Res. 2006 Oct 15;66(20):10064-72
17047070
Biochem Pharmacol. 2002 Mar 15;63(6):1085-97
11931841
Trends Biotechnol. 2007 Jan;25(1):33-9
17084931
J Clin Oncol. 2000 Jul;18(13):2505-14
10893280
J Urol. 1999 May;161(5):1521-4
10210387