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Biochem Biophys Res Commun. 2002 Jan 11;290(1):552-7.

Protein kinase C induces motility of breast cancers by upregulating secretion of urokinase-type plasminogen activator through activation of AP-1 and NF-kappaB.

Author information

1
Cancer Research Laboratory, Methodist Research Institute, Clarian Health Partners Incorporated, 1633 North Capitol Avenue, MT 350, Indianapolis, IN 46202, USA. dsliva@clarian.org

Abstract

Cell migration is a crucial process in cancer metastasis that does not require extracellular matrix degradation-a characteristic of cell invasion. The urokinase-type plasminogen activator (uPA) system is responsible for invasion through uPA enzymatic activity and for migration through the binding of uPA to the uPA receptor (uPAR). Constitutively high levels of uPA are characteristic of the highly metastatic breast cancer cells MDA-MB-231, but the mechanisms underlying constitutive uPA expression are not fully characterized. In this report we show that inhibition of protein kinase C (PKC) represses constitutive (nonstimulated) migration of MDA-MB-231 cells. Bisindolylmaleimide I (Bis I) inhibits cell migration and constitutive activation of transcription factors AP-1 and NF-kappaB, suggesting that PKC is responsible for increased migration of MDA-MB-231 cells. It is clear that the inhibition of PKC occurs at the transactivation levels of AP-1 and NF-kappaB because Bis I did not affect constitutive DNA binding of AP-1 and NF-kappaB. Furthermore, we show that Bis I did not affect the levels of IkappaBalpha, suggesting that PKC-mediated cell migration is IkappaBalpha independent. Finally, we demonstrate that constitutive secretion of uPA is repressed by Bis I, implying an important role for AP-1 and NF-kappaB in cell migration. Our data demonstrate a connection among PKC, constitutively active AP-1 and NF-kappaB, constitutive secretion of uPA, and cell migration of highly invasive breast cancer cells. Thus, PKC controls cell motility by regulating expression of uPA through the activation of AP-1 and NF-kappaB. The disruption of PKC, AP- 1, and NF-kappaB signaling in breast cancer may be used to develop therapies for breast cancer prevention and intervention by reducing the secretion of uPA.

PMID:
11779207
DOI:
10.1006/bbrc.2001.6225
[Indexed for MEDLINE]

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