Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway.
Dietary phytochemicals are known to exhibit a variety of anticarcinogenic properties. This study investigated the chemopreventive activity of blueberry extract in triple-negative breast cancer cell lines in vitro and in vivo. Blueberry decreased cell proliferation in HCC38, HCC1937, and MDA-MB-231 cells with no effect on the nontumorigenic MCF-10A cell line. Decreased metastatic potential of MDA-MB-231 cells by blueberry was shown through inhibition of cell motility using wound-healing assays and migration through a polyethylene terephthalate membrane. Blueberry treatment decreased the activity of matrix metalloproteinase-9 and the secretion of urokinase-type plasminogen activator while increasing tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 secretion in MDA-MB-231 conditioned medium as shown by Western blotting. Cell signaling pathways that control the expression/activation of these processes were investigated via Western blotting and reporter gene assay. Treatment with blueberry decreased phosphatidylinositol 3-kinase (PI3K)/AKT and NFkappaB activation in MDA-MB-231 cells, where protein kinase C and extracellular signal-regulated kinase (ERK) were not affected. In vivo, the efficacy of blueberry to inhibit triple-negative breast tumor growth was evaluated using the MDA-MB-231 xenograft model. Tumor weight and proliferation (Ki-67 expression) were decreased in blueberry-treated mice, where apoptosis (caspase-3 expression) was increased compared with controls. Immunohistochemical analysis of tumors from blueberry-fed mice showed decreased activation of AKT and p65 NFkappaB signaling proteins with no effect on the phosphorylation of ERK. These data illustrate the inhibitory effect of blueberry phytochemicals on the growth and metastatic potential of MDA-MB-231 cells through modulation of the PI3K/AKT/NFkappaB pathway.
Adams
Lynn S
LS
Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Phung
Sheryl
S
Yee
Natalie
N
Seeram
Navindra P
NP
Li
Liya
L
Chen
Shiuan
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001628:Beverages; D029798:Blueberry Plants; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000032:analysis / Q000494:pharmacology; D005638:Fruit / Q000737:chemistry*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010636:Phenols / Q000032:analysis / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010936:Plant Extracts / Q000032:analysis / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D059808:Polyphenols; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; D010636:Phenols; D010936:Plant Extracts; D017395:Plasminogen Activator Inhibitor 1; D059808:Polyphenols; D019715:Tissue Inhibitor of Metalloproteinase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
Oncogene. 2006 Mar 23;25(13):1922-30
16449979
J Nutr Biochem. 2008 May;19(5):313-9
17683926
Histopathology. 2008 Jan;52(1):108-18
18171422
Thromb Haemost. 2003 Sep;90(3):538-48
12958624
Int J Mol Med. 2008 May;21(5):577-84
18425349
J Nutr Biochem. 2009 Sep;20(9):663-76
18824345
Mol Carcinog. 2008 Apr;47(4):286-94
18085529
Cancer Res. 2007 Apr 1;67(7):3310-9
17409440
J Oral Pathol Med. 2007 Nov;36(10):588-93
17944751
Am J Pathol. 2002 Jan;160(1):237-46
11786417
Clin Cancer Res. 2008 Dec 15;14(24):8010-8
19088017
J Agric Food Chem. 2009 Feb 25;57(4):1291-8
19178296
Nutr Cancer. 2008;60(6):744-56
19005974
Cancer Res. 2004 Feb 1;64(3):830-5
14871808
Int J Cancer. 2010 Jul 1;127(1):239-44
19876913
J Agric Food Chem. 2003 Mar 12;51(6):1718-23
12617611
Cancer Sci. 2009 Sep;100(9):1668-74
19538528
J Agric Food Chem. 2010 Apr 14;58(7):3965-9
20014760
Cancer Prev Res (Phila). 2009 Jan;2(1):84-93
19139022
Cancer Prev Res (Phila). 2009 Mar;2(3):187-94
19258544
Int J Dev Biol. 2004;48(5-6):411-24
15349816
J Agric Food Chem. 2008 Feb 13;56(3):627-9
18211023
J Agric Food Chem. 2006 Dec 13;54(25):9329-39
17147415
Nutr Cancer. 2008;60(2):227-34
18444155
Eur J Biochem. 1999 Jul;263(2):295-304
10406935
J Thromb Haemost. 2005 Jan;3(1):35-45
15634264
Toxicol Appl Pharmacol. 2008 Jan 15;226(2):178-91
17961621
J Agric Food Chem. 2004 May 5;52(9):2512-7
15113149
Br J Cancer. 2008 Apr 22;98(8):1348-56
18362935
Biochem Biophys Res Commun. 2002 Nov 8;298(4):603-12
12408995
Lancet Oncol. 2007 Mar;8(3):235-44
17329194
Enzyme. 1988;40(2-3):158-72
3049065
Toxicol Appl Pharmacol. 2005 Dec 1;209(2):105-13
15953625
Am J Pathol. 2002 Dec;161(6):1991-6
12466114
Neoplasia. 2005 Feb;7(2):128-40
15802018
Nutr Cancer. 2007;58(2):205-12
17640167
Am J Surg Pathol. 2000 Feb;24(2):197-202
10680887
FASEB J. 2008 Mar;22(3):659-61
17942826
J Nutr Biochem. 2006 Feb;17(2):117-25
16111875
Mol Cancer Ther. 2006 Nov;5(11):2666-75
17121913
Biochem Biophys Res Commun. 2002 Jan 11;290(1):552-7
11779207
Antioxid Redox Signal. 2009 Jan;11(1):47-58
18817478
Cancer Lett. 2006 Apr 28;235(2):248-59
15975709
Sci Signal. 2008 Jul 08;1(27):re6
18612141
Nutr Cancer. 2008;60 Suppl 1:61-9
19003582
Cancer Sci. 2007 Dec;98(12):1889-92
17892507
Breast Cancer Res Treat. 2010 Jul;122(1):45-53
19701705
J Agric Food Chem. 2002 May 22;50(11):3156-60
12009979