Theaflavins retard human breast cancer cell migration by inhibiting NF-kappaB via p53-ROS cross-talk.
The present study demonstrates that theaflavins exploit p53 to impede metastasis in human breast cancer cells. Our data suggest that p53-dependent reactive oxygen species (ROS) induce p53-phosphorylation via p38MAPK in a feedback loop to inhibit IkappaBalpha-phosphorylation and NF-kappaB/p65 nuclear translocation, thereby down-regulating the metastatic proteins metalloproteinase (MMP)-2 and MMP-9. When wild-type p53-expressing MCF-7 cells are transfected with p53 short-interfering RNA, or treated with a pharmacological inhibitor of ROS, theaflavins fail to inhibit NF-kappaB-mediated cell migration. On the other hand, NF-kappaB over-expression bestows MCF-7 cells with resistance to the anti-migratory effect of theaflavins. These results indicate that inhibition of NF-kappaB via p53-ROS crosstalk is a pre-requisite for theaflavins to accomplish the anti-migratory effect in breast cancer cells.
Adhikary
Arghya
A
Division of Molecular Medicine, Bose Institute, P1/12 CIT Scheme VIIM, Kolkata, India.
Mohanty
Suchismita
S
Lahiry
Lakshmishri
L
Hossain
Dewan Md Sakib
DM
Chakraborty
Samik
S
Das
Tanya
T
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology*; D044946:Biflavonoids / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000378:metabolism / Q000556:secondary*; D002392:Catechin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009362:Neoplasm Metastasis; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D044946:Biflavonoids; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C056068:theaflavin; D002392:Catechin; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9