NS 398 radiosensitizes an HNSCC cell line by possibly inhibiting radiation-induced expression of COX-2.
Journal - International journal of radiation oncology, biology, physics (United States )
PURPOSE: Cyclooxygenase-2 (COX-2) protein is frequently elevated in squamous cell carcinoma of the head and neck (HNSCC). The aim of this study was to determine if COX-2 inhibitors have radiosensitizing effects in HNSCC and understand the mechanism by which this occurs. MATERIALS AND METHODS: The radiosensitizing effects of a selective COX-2 inhibitor, NS398, on a HNSCC cell line HEp3, were determined using clonogenic survival assay. Cells were pretreated with the dose of NS398 at which 50% growth inhibition occurred (IC(50)) and then irradiated. COX-2 protein and mRNA were then determined in the presence and absence of NS398. RESULTS: NS398 significantly decreased (p < 0.0001) the calculated survival fraction (SF) for all radiation doses (0.79 to 0.41 at 2 Gy). A significant increase in COX-2 protein of 2.8 fold for 2 Gy and 3.5 fold for 6 Gy was noted 48 h after radiation. Interestingly, the upregulation of COX-2 protein with radiation was suppressed when cells were pretreated with NS398. Quantitative reverse transcriptase polymerase chain reaction showed no significant corresponding increase in COX-2 mRNA at 48 h with ionizing radiation. CONCLUSIONS: The radiosensitizing effect of NS398 could be due to inhibition of radiation-induced COX-2 upregulation by this drug. NS398, known as an inhibitor of COX-2 enzyme activity, down-regulated COX-2 protein expression, which may indicate that NS398 can act upstream of COX-2, and this change appears to be post-transcriptional.
|ISSN : ||0360-3016|
|Mesh Heading : ||Carcinoma, Squamous Cell Cell Line, Tumor Cell Survival Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Drug Screening Assays, Antitumor Head and Neck Neoplasms Humans Isoenzymes Membrane Proteins Neoplasm Proteins Nitrobenzenes Prostaglandin-Endoperoxide Synthases RNA, Messenger Radiation-Sensitizing Agents Sulfonamides Up-Regulation radiation effects antagonists & inhibitors antagonists & inhibitors metabolism|
|Mesh Heading Relevant : ||enzymology radiotherapy pharmacology enzymology radiotherapy metabolism metabolism pharmacology metabolism pharmacology pharmacology|
Modulation of the Cell Growth Regulator mTOR by Epstein-Barr Virus-Encoded LMP2A
Journal - Journal of Virology
Control of translation initiation is one means by which cells regulate growth and proliferation, with components of the protein-synthesizing machinery having oncogenic potential. Expression of latency protein LMP2A by the human tumor virus Epstein-Barr virus (EBV) activates phosphatidylinositol 3-kinase/Akt located upstream of an essential mediator of growth signals, mTOR (mammalian target of rapamycin). We show that mTOR is activated by expression of LMP2A in carcinoma cells, leading to wortmannin- and rapamycin-sensitive inhibition of the negative regulator of translation, eukaryotic initiation factor 4E-binding protein 1, and increased c-Myc protein translation. Intervention by this DNA tumor virus in cellular translational controls is likely to be an integral component of EBV tumorigenesis.