Abstract. Hypoxia-inducible factor-1 (HIF-1) has a central role in cellular responses to hypoxia, including the transcriptional activation of a number of genes involved in angiogenesis in tumors. We found that curcumin, a natural, biologically active compound isolated from the commonly used spice turmeric, significantly decreases hypoxia-induced HIF-1· protein levels in HepG2 hepatocellular carcinoma cells. Moreover, curcumin suppressed the transcriptional activity of HIF-1 under hypoxia, leading to a decrease in the expression of vascular endothelial growth factor (VEGF), a major HIF-1 target angiogenic factor. Curcumin also blocked hypoxia-stimulated angiogenesis in vitro and down-regulated HIF-1· and VEGF expression in vascular endothelial cells. These findings suggest that curcumin may play pivotal roles in tumor suppression via the inhibition of HIF-1·-mediated angiogenesis.

No abstract

Visfatin has been originally identified as a growth factor for early stage B cells and recently known as an adipokine. Here, we report that hypoxia induces the visfatin mRNA and protein levels in MCF7 breast cancer cells. We also demonstrate that induction of visfatin gene is regulated by hypoxia-inducible factor-1a (HIF-1a). Moreover, 50 -flanking promoter region of human visfatin gene contains two functional HIF responsive elements (HREs), activating the expression of visfatin. Mutation of these HREs in the visfatin promoter abrogates activation of a luciferase reporter gene driven by visfatin promoter under hypoxia. Taken together, our results demonstrate that visfatin is a new hypoxia-inducible gene of which expression is stimulated through the interaction of HIF-1 with HRE sites in its promoter region.

P. gingivalis is a major pathogen that is involved in the onset and progression of periodontal disease. This study investigated the effect of resveratrol, a naturally occurring polyphenol, on P. gingivalis LPS-accelerated vascular inflammation, a key step in the progression of periodontitis. Resveratrol significantly inhibited the P. gingivalis LPS-induced adhesion of leukocytes to endothelial cells and to the aortic endothelium by down-regulating the cell adhesion molecules, ICAM-1 and VCAM-1. Moreover, the inhibition of the P. gingivalis LPS-induced cell adhesion molecules by resveratrol was mainly mediated by nuclear factor-kappaB (NF-kappaB). Resveratrol suppressed P. gingivalis LPS-stimulated IkappaBalpha phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB in HMECs. Overall, these findings suggest that resveratrol significantly attenuates the P. gingivalis LPS-induced monocyte adhesion to the endothelium by suppressing the expression of the NF-kappaB-dependent cell adhesion molecules, suggesting its therapeutic role in periodontal pathogen-induced vascular inflammation.

TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in cancer cells without harming most normal cells. Currently, multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL (rhTRAIL) and agonistic antibodies that target death receptors (DRs) 4 or 5. It is encouraging that these products have shown a tolerated safety profile in early phase studies. However, their therapeutic potential is likely limited by the emergence of tumor drug resistance phenomena. Increasing evidence indicates that TRAIL DRs are deficient on the plasma membrane of some cancer cells despite their total protein expression. Notably, the lack of surface DR4/DR5 is sufficient to render cancers resistant to TRAIL-induced apoptosis, regardless of the status of other apoptosis signaling components. The current review highlights recent findings on the dynamic expression of TRAIL death receptors, including the regulatory roles of endocytosis, autophagy, and Ras GTPase-mediated signaling events. This information could aid in the identification of novel predictive biomarkers of tumor response as well as the development of combinational drugs to overcome or bypass tumor drug resistance to TRAIL receptor-targeted therapies.