Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel  -methylene- -butyrolactone derivatives

Abstract

The transcription factor nuclear factor-kappaB (NF-kappaB) is a regulator related to cellular inflammation, immune responses and carcinogenesis. Therefore, components of the NF-kappaB-activating singnaling pathways are frequent targets for the anti-inflammatory and anticancer agents. In this study, CYL-19 s and CYL-26z, two synthetic alpha-methylene-gamma-butyrolactone derivatives, were shown to inhibit the tumor necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule-1 (ICAM-1) expression in human A549 alveolar epithelial cells and the adhesion of U937 cells to these cells. RT-PCR analysis also demonstrated their inhibitory effects on TNF-alpha-induced ICAM-1 mRNA expression. TNF-alpha-induced ICAM-1 and NF-kappaB-dependent promoter activities were attenuated by CYL-19 s and CYL-26z. ICAM-1 promoter activities induced by the over-expression of wild-type NF-kappaB-inducing kinase and IkappaB kinase beta (IKKbeta) were also inhibited by both compounds. Furthermore, CYL-19 s and CYL-26z inhibited the TNF-alpha-induced phosphorylation and degradation of IkappaBalpha and NF-kappaB-specific DNA-protein binding activity via targeting IKK complex directly, without any effect on the activations of other kinases such as ERK1/2 and p38. In addition to ICAM-1 expression, CYL-19 s and CYL-26z also suppressed other NF-kappaB-mediated gene expressions such as matrix metalloproteinase-9 (MMP-9) mRNA and cyclooxygnease-2 (COX-2) protein. In Matrigel assays, ICAM-1 and COX-2 expressions induced by TNF-alpha elicited A549 and NCI-H292 cell invasion, respectively, and these effects were inhibited by both compounds. In summary, our data demonstrated that CYL-19 s and CYL-26z down-regulate the TNF-alpha-induced inflammatory genes expression through suppression of IKK activity and NF-kappaB activation. These agents may be effective in the anti-inflammatory and anticancer therapy.

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

“…The introduction of exogenous PGE 2 reversed the inhibitory effect of NS-398. Similar positive correlation between PGs productions and tumor invasiveness was observed in the lung cells (32). Cell line transfected with COX-2 (AGS/ COX-2) also exhibited high invasiveness and angiogenesis.…”

“…COX-2 may play a role as survival factor in protecting cells from apoptosis (30). Furthermore, functions like the encouragement of cell proliferation (31), the induction of tumor cell invasion (32,33), the stimulation of angiogenesis (11), and the inhibition of immunosurveillance (34) have also been described. SC-236, a selective COX-2 inhibitor, was effective in reducing angiogenesis driven by the basic fibroblast growth factor in a Matrigel model (35).…”

Transfection of NF-κB decoy oligodeoxynucleotide suppresses pulmonary metastasis by murine osteosarcoma

“…35 VEGF has been reported to induce the proliferation of endothelial cells and increased vascular permeability, 10 whereas ICAM-1 is known to have an important role in lymphatic and vascular invasion, and subsequent adhesion to other tissues. 36 It has been reported that the expression of VEGF and/or ICAM-1 is correlated to the malignancy, or metastatic potential of tumors including osteosarcoma. 37,38 In our study, the mRNA levels of VEGF and ICAM-1 were significantly decreased by transfection of NF-kB decoy ODN, indicating that the metastatic potential of LM8 cells was decreased by the transfection of NF-kB decoy ODN.…”

ICAM-3 enhances the migratory and invasive potential of human non-small cell lung cancer cells by inducing MMP-2 and MMP-9 via Akt and CREB

“…ICAM molecules may target and block tumor progression by stimulation of an immune response such as leukocyte activation (15,16). Conversely, other investigations have shown that ICAM molecules are involved in cancer malignancy because their increased expressions are associated with a poor diagnosis, lower survival rates and metastasis in some cancers including melanoma, breast cancer and leukemia (17)(18)(19)(20)(21)(22)(23)(24). We have also reported that an increase of ICAM-3 expression in several cancer cells and specimens of cervical cancer patients induced enhanced radio-resistance by the activation of focal adhesion kinase (FAK) (25) and promoted cancer cell proliferation by the activation of Akt and p44/42 MAPK (26).…”