Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA

Abstract

The Rel/NF-kB transcription factors regulate the expression of many genes. The activity of RelA, a member of the Rel/NF-kB transcription factor family, is constitutively activated in the majority of pancreatic adenocarcinomas and cell lines. We report that the urokinase-type plasminogen activator (uPA), one of the critical proteases involved in tumor invasion and metastasis, is overexpressed in pancreatic tumor cells and its overexpression is induced by constitutive RelA activity. The uPA promoter contains an NF-kB binding site that directly mediates the induction of uPA expression by RelA. Expression of a dominant-negative IkBa mutant inhibits kB site-dependent transcriptional activation of a uPA promoter-CAT reporter gene. Treating the pancreatic tumor cell lines with the known NF-kB inhibitors, dexamethasone and n-tosylphenyalanine chloromethyl ketone (TPCK), abolishes constitutive RelA activity and uPA overexpression. These results show that uPA is one of the downstream target genes induced by constitutively activated RelA in human pancreatic tumor cells, and suggests that constitutive RelA activity may play a critical role in tumor invasion and metastasis. Inhibition of constitutive RelA in pancreatic tumor cells may reduce their invasive and metastatic potential.

Knocking Off SOCS Genes in the Mammary Gland

“…In the embryonic limb bud, NFkB family members have been shown to modulate epithelial-mesenchymal interactions, 46 while a number of in vitro studies have revealed that NFkB can regulate the expression of MMP-1, MMP-3, MMP-9 and urokinase-type plasminogen activator. [47][48][49][50] Similar to MMP activity, NFkB DNA-binding activity is also maximal during the second phase of involution. 51,52 Socs3 is most closely related to Socs1 and is induced by prolactin with similar kinetics, leading to inhibition of Stat5 activation in mammary epithelial cells.…”

Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP

“…For example, recent reports show that XIAP regulates ubiquitin-dependent activation of IkB kinase via its RING finger, which then activates NFkB. 21 Through the canonical and noncanonical signaling pathways, NFkB drives the expression of many downstream genes including uPA, 22 IL-1b, 23 CREB, and TNF-a. [24][25][26] These proteins can, in turn, increase the expression of VEGF.…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…Additionally, it has been reported that autocrine production of IL-1a regulates NF-kB activation in pancreatic cancer cells (Niu et al, 2004). NF-kB-regulated gene targets that encode proteins potentially relevant to the maintenance and invasion of pancreatic cancer cells are proposed to be GADD45a and urokinase-type plasminogen activator (Wang et al, 1999b;Schneider et al, 2006).…”