| 2983 Induction of Apoptosis in OSCC Cells by Proteasome Inhibitor PS-341 | ||
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A. FRIBLEY, University of Michigan, Ann Arbor, USA, and C.-Y. WANG, University of Michigan, Ann Arbor, USA Objective: This study is to elucidate molecular mechanisms by which the proteasome inhibitor PS-341 inhibits oral squamoous cell carcinoma (OSCC) growth. PS-341 represents a novel class of anti-cancer drugs which has bas been shown to potently inhibit the growth and/or progression of human cancers, including OSCC. However, the underlying mechanism by which PS-341 inhibits tumor cell growth is unclear. In this study, we hypothesized that PS-341 inhibited OSCC growth by the induction of apoptosis. Methods: DNA laddering, caspase assays and Western blot analysis were utilized to evaluate apoptosis induced by PS-341 in OSCC cells. Northern blot analysis, Real-time PCR and microarray analysis were performed to determine gene expression profile induced by PS-341. Results: We found that PS-341 potently induced apoptosis in at least eight human OSCC cell lines, including two cisplatin-resistant cell lines. PS-341 stimulation rapidly activated caspases-2, -3 and -9 in OSCC cells, suggesting that these caspases may play a critical role in OSCC cell apoptosis. In addition to caspase activation, we observed that a pro-apoptotic molecule Bax was essential for PS-341-mediated apoptosis using genetically-modified cell lines. Finally, our microarray study found that anti-apoptotic genes, which were dependent on the transcription factor nuclear factor-kappa B (NF-kB), were inhibited by PS-341. Unexpectedly, a clustering of stress-responsive genes, including heat shock proteins, growth and DNA damage proteins and cyclin-dependent kinase inhibitors, was strongly up-regulated by PS-341. Currently, we are characterizing functional roles of these genes in PS-341-mediated tumor inhibition. Conclusion: Our results suggest that PS-341 may inhibit OSCC growth through the induction of apoptosis. In addition to the inhibition of NF-kB, PS-341 may induce OSCC cell apoptosis by stimulating transcription. This work was supported by NICDR grants RO1-DE and RO1-DE to C.-Y. W and T32-DE0757 to A.F. | ||
| Seq #324 - Senior Category 10:15 AM-11:30 AM, Saturday, 13 March 2004 Hawaii Convention Center Exhibit Hall 1-2 | ||
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