NF‐κB activity blockade impairs the angiogenic potential of human pancreatic cancer cells

Abstract

Key words: pancreatic cancer; NF-B; angiogenesis; metastasis; apoptosisMetastatic pancreatic adenocarcinoma is a deadly disease, the aggressive nature of which is related to several abnormalities in growth factors and their receptors that affect the downstream signal transduction pathways involved in the control of growth and differentiation. 1,2 Other contributing molecular changes in pancreatic adenocarcinoma include activation of oncogenes and inactivation of tumor suppressor genes. 3,4 These perturbations confer a tremendous survival and growth advantage to pancreatic cancer cells. Understanding the biology and pathogenesis of pancreatic cancer is crucial to reversing the metastatic biology of this disease. As with other solid tumors, the growth and metastasis of pancreatic adenocarcinoma are dependent on angiogenesis. 5 Of the numerous angiogenic factors discovered so far, vascular endothelial growth factor (VEGF) 6 -8 and, most recently, interleukin-8 (IL-8) 9,10 have been identified as key mediators of pancreatic tumor angiogenesis.VEGF has been shown to induce the proliferation of endothelial cells, increase vascular permeability and induce the production of plasminogen activators by these cells. 11,12 IL-8, a chemoattractant cytokine, has been shown to attract and activate neutrophils in inflammatory regions and be angiogenic. 13,14 The mechanism of regulation of constitutive expression of these genes in malignant pancreatic cancer cells is not clear, however. Recent studies demonstrated that the pleiotropic transcription factor nuclear factor-B (NF-B) regulates the expression of multiple genes, including IL-8 and VEGF, in several types of cells. 10,14 -17 NF-B has been shown to be constitutively activated in pancreatic cancer cells; 18,19 NF-B activity can also be elevated by several stress factors in human pancreatic cancer cells, such as hypoxia, acidosis, nitric oxide and proinflammatory cytokines. 20 Accumulating evidence from in vitro and in vivo studies suggests an important role for NF-B in the regulation of apoptosis, cell adhesion and oncogenesis. [21][22][23] However, the critical role of constitutive NF-B activity in pancreatic cancer angiogenesis has not been investigated.NF-B is an inducible dimeric transcription factor belonging to the Rel/NF-B family of transcription factors whose prototype in most nonlymphoid cells is a heterodimer composed of the RelA (p65) and NF-B1 (p50) subunits. 24 -26 NF-B activation involves its release from a cytoplasm inhibitor of NF-B (IB); it subsequently translocates to the nucleus, where it binds to cognate sequences in the promoter region of multiple genes. Regulation of gene expression by NF-B is controlled mainly by the inhibitory IB proteins, which include IB␣. 24,26 Upon stimulation, IB␣ is rapidly phosphorylated and degraded via the ubiquitin-proteasome pathway, permitting activation and nuclear importation of NF-B. Researchers engineered dominant-negative mutant forms of IB␣ (IB␣M) that could not be phosphorylated and degraded and thus constitutively...

Anti-angiogenic effect of total saponins of Rhizoma Dioscorea nipponica on collagen induced-arthritis in rats

“…NF-κB has been shown to be widely expressed in RA synovial cells (36), which is consistent with the present results. Previous studies have shown that NF-κB may be involved in regulating angiogenesis (37), and that inhibiting the activity of NF-κB in pancreatic cancer may prevent the formation of new blood vessels (38). The present study showed that the DNA-binding activity of NF-κB p65 could be inhibited by TSRDN.…”

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

“…Previous studies have demonstrated that the Notch signaling pathway is critical in cell proliferation and apoptosis (30,31). Among the Notch genes, Notch-1 has been reported to be involved in the migration and invasion of cancer cells (32) and to exhibit crosstalk with nuclear factor κB (NF-κB), another important regulatory pathway in the processes of tumor cell invasion and metastasis (33)(34)(35)(36)(37). The MMPs, a family of associated enzymes that degrade the extracellular matrix, are also considered to be important in facilitating tumor invasion (38).…”

Downregulation of the Notch signaling pathway inhibits hepatocellular carcinoma cell invasion by inactivation of matrix metalloproteinase-2 and -9 and vascular endothelial growth factor

“…The Notch signaling pathway can regulate MMP-2, MMP-9 and VEGF (22,(36)(37)(38)(39)(40), which are important in the processes of invasion and metastasis of tumor. In the current study, the invasion capabilities of HepG2 and MHCC97H cells treated with DAPT decreased.…”