title: Inhibition of SIRT2 potentiates the anti-motility activity of taxanes: implications for antineoplastic combination therapies.
abstract: 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.
authors.affiliation: Tumor Angiogenesis Unit, Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Bonezzi
authors.forename: Dorina
authors.initials: D
authors.lastname: Belotti
authors.forename: Brian J
authors.initials: BJ
authors.lastname: North
authors.forename: Carmen
authors.initials: C
authors.lastname: Ghilardi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Borsotti
authors.forename: Andrea
authors.initials: A
authors.lastname: Resovi
authors.forename: Paolo
authors.initials: P
authors.lastname: Ubezio
authors.forename: Antonella
authors.initials: A
authors.lastname: Riva
authors.forename: Raffaella
authors.initials: R
authors.lastname: Giavazzi
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Giulia
authors.initials: G
authors.lastname: Taraboletti
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D043823:Taxoids; D056565:Sirtuin 2