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Item Autotaxin expression and its connection with the TNF-alpha-NF-κB axis in human hepatocellular carcinoma(BMC, 2010-03-31) Wu, Jian-Min; Xu, Yan; Skill, Nicholas J.; Sheng, Hongmiao; Zhao, Zhenwen; Yu, Menggang; Saxena, Romil; Maluccio, Mary A.; Surgery, School of MedicineBackground Autotaxin (ATX) is an extracellular lysophospholipase D that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been shown to be involved in many cancers. However, the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma (HCC) remain elusive. Results In this study, ATX expression was evaluated in tissues from 38 human HCC and 10 normal control subjects. ATX was detected mainly in tumor cells within tissue sections and its over-expression in HCC was specifically correlated with inflammation and liver cirrhosis. In addition, ATX expression was examined in normal human hepatocytes and liver cancer cell lines. Hepatoma Hep3B and Huh7 cells displayed stronger ATX expression than hepatoblastoma HepG2 cells and normal hepatocytes did. Proinflammtory cytokine tumor necrosis factor alpha (TNF-α) promoted ATX expression and secretion selectively in Hep3B and Huh7 cells, which led to a corresponding increase in lysophospholipase-D activity. Moreover, we explored the mechanism governing the expression of ATX in hepatoma cells and established a critical role of nuclear factor-kappa B (NF-κB) in basal and TNF-α induced ATX expression. Further study showed that secreted enzymatically active ATX stimulated Hep3B cell invasion. Conclusions This report highlights for the first time the clinical and biological evidence for the involvement of ATX in human HCC. Our observation that links the TNF-α/NF-κB axis and the ATX-LPA signaling pathway suggests that ATX is likely playing an important role in inflammation related liver tumorigenesis.Item Parthenolide Sensitizes Cells to X-Ray-Induced Cell Killing through Inhibition of NF-κB and Split-Dose Repair(Radiation Research Society, 2007-12) Mendonca, Marc S.; Chin-Sinex, Helen; Gomez-Millan, Jaime; Datzman, Nicholas; Hardacre, Michael; Comerford, Kathleen; Nakshatri, Harikrishna; Nye, Monica; Benjamin, Laura; Mehta, Sachin; Patino, Fatima; Sweeney, ChristopherMendonca, M. S., Chin-Sinex, H., Gomez-Millan, J., Datzman, N., Hardacre, M., Comerford, K., Nakshatri, H., Nye, M., Benjamin, L., Mehta, S., Patino, F. and Sweeney, C. Parthenolide Sensitizes Cells to X-Ray-Induced Cell Killing through Inhibition of NF-κB and Split-Dose Repair. Radiat. Res. 168, 689–697 (2007).Human cancers have multiple alterations in cell signaling pathways that promote resistance to cytotoxic therapy such as X rays. Parthenolide is a sesquiterpene lactone that has been shown to inhibit several pro-survival cell signaling pathways, induce apoptosis, and enhance chemotherapy-induced cell killing. We investigated whether parthenolide would enhance X-ray-induced cell killing in radiation resistant, NF-κB-activated CGL1 cells. Treatment with 5 μM parthenolide for 48 to 72 h inhibited constitutive NF-κB binding and cell growth, reduced plating efficiency, and induced apoptosis through stabilization of p53 (TP53), induction of the pro-apoptosis protein BAX, and phosphorylation of BID. Parthenolide also enhanced radiation-induced cell killing, increasing the X-ray sensitivity of CGL1 cells by a dose modification factor of 1.6. Flow cytometry revealed that parthenolide reduced the percentage of X-ray-resistant S-phase cells due to induction of p21waf1/cip1 (CDKN1A) and the onset of G1/S and G2/M blocks, but depletion of radioresistant S-phase cells does not explain the observed X-ray sensitization. Further studies demonstrated that the enhancement of X-ray-induced cell killing by parthenolide is due to inhibition of split-dose repair.