Protection against DNA damage-induced apoptosis by the angiogenic factor thymidine phosphorylase

Thymidine phosphorylase (TP) is involved both in pyrimidine nucleoside metabolism and in angiogenesis. TP also conferred the resistance to hypoxia-induced apoptosis of the cancer cells. In U937 cells, DNA damage-inducing agents significantly enhanced the expression of TP. Cell lines stably transfected with TP cDNA were more resistant to the DNA damage-inducing agents than the mock-transfected cells and showed augmented activity of Akt. The cytoprotective function of TP against DNA damage was independent of its enzymatic activity. The resistance to apoptosis was partially abrogated by treatment with the phosphatidyl inositol 3-kinase (PI3K) inhibitors, suggesting that the cytoprotective function of TP is mediated, at least in part, by regulation of the PI3K/Akt pathway. These findings indicate that TP expression in increased by various stress including DNA damage and that TP molecules confer resistance to DNA damage-induced apoptosis in cancer cells.     

Growth compensatory role of sulindac sulfide-induced thrombospondin-1 linked with ERK1/2 and RhoA GTPase signaling pathways

Previously, we reported that non-steroidal anti-inflammatory drugs (NSAIDs) suppress cellular invasion which was mediated by thrombospondin-1 (TSP-1). As the extending study of the previous observation, we investigated the effect of NSAID-induced TSP-1 on the cellular growth and its related signaling transduction of the TSP-1 production. Among diverse NSAIDs, sulindac sulfide was most potent of inducing the human TSP-1 protein expression. Functionally, induced TSP-1 expression was associated with the growth-compensatory action of NSAID. TSP-1 expression was also elevated by mitogenic signals of ERK1/2 and RhoA GTPase pathway which had also growth-promotive capability after sulindac sulfide treatment. These findings suggest the possible mechanism through which tumor cells can survive the chemopreventive action of NSAIDs or the normal epithelium can reconstitute after NSAID-mediated ulceration in a compensatory way.     

Effects of growth factors and kinase inhibitors on the properties of human adipose-stromal cells in different culture conditions

The best-fit environments for the proliferation and differentiation of human adipose tissue-derived stromal cells (hADSCs) may require specific media and stimuli. The characteristics of hADSCs cultured in different media might be different. We evaluated the effects of growth factors on the proliferation and differentiation of hADSCs and compared the effects of these growth factors on hADSCs cultured in different serum-contained media. The effects of kinase inhibitors on the proliferation of hADSCs were also examined. The combination of insulin-transferrin-selenium (ITS) and fibroblast growth factor (FGF) induced the greatest increase in proliferation, while the combination of ITS and epidermal growth factor (EGF) showed the second-greatest effect in the human serum (HS)-contained media. By contrast, in the fetal bovine serum (FBS)-contained media, ITS had little effect while FGF had better results than the combination of ITS and EGF. The inhibitory potency of the kinase inhibitors was different in the two different media. These results suggest that hADSCs may have different characteristics according to the culture conditions, and that extrapolations of results from animal studies, using FBS media, may not correlate to findings in human studies using HS.     

Cdc42 and Rac1 are necessary for autotaxin-induced tumor cell motility in A2058 melanoma cells

Autotaxin (ATX) is a strong motogen that can increase invasiveness and angiogenesis. In the present study, we investigated the signal transduction mechanism of ATX-induced tumor cell motility. Unlike N19RhoA expressing cells, the cells expressing N17Cdc42 or N17Rac1 showed reduced motility against ATX. ATX activated Cdc42 and Rac1 and increased complex formation between these small G proteins and p21-activated kinase (PAK). Furthermore, ATX phosphorylated focal adhesion kinase (FAK) that was not shown in cells expressing dominant negative mutants of Cdc42 or Rac1. Collectively, these data strongly indicate that Cdc42 and Rac1 are essential for ATX-induced tumor cell motility in A2058 melanoma cells, and that PAK and FAK might be also involved in the process.