Taxanes are potent inhibitors of cell motility, a property implicated in their 
antiangiogenic and antimetastatic activity and unrelated to their 
antiproliferative effect. The molecular mechanism of this anti-motility activity 
is poorly understood. In this study, we found that paclitaxel induced tubulin 
acetylation in endothelial and tumor cells, at concentrations that affected cell 
motility but not proliferation (10(-8) to 10(-9) M, for 4 hours). Induction of 
tubulin acetylation correlated with inhibition of motility but not proliferation 
based on a comparison of highly and poorly cytotoxic taxanes (paclitaxel and 
IDN5390) and tumor cell lines sensitive and resistant to paclitaxel (1A9 and 1A9 
PTX22). Consistent with the hypothesis that tubulin deacetylase activity might 
affect cell response to the anti-motility activity of taxanes, we found that 
overexpression of the tubulin deacetylase SIRT2 increased cell motility and 
reduced cell response to the anti-motility activity of paclitaxel. Conversely, 
the SIRT2 inhibitor splitomicin reduced cell motility and potentiated the 
anti-motility activity of paclitaxel. The inhibitory effect was further 
potentiated by the addition of the HDAC6 inhibitor trichostatin A. Paclitaxel 
and splitomicin promoted translocation into the nucleus--and hence 
activation--of FOXO3a, a negative regulator of cell motility. This study 
indicates a role for SIRT2 in the regulation of cell motility and suggests that 
therapies combining sirtuin inhibitors and taxanes could be used to treat cell 
motility-based pathologic processes such as tumor angiogenesis, invasion, and 
metastasis.