title: Stathmin potentiates vinflunine and inhibits Paclitaxel activity.
abstract: Cell biology and crystallographic studies have suggested a functional link between stathmin and microtubule targeting agents (MTAs). In a previous study we showed that stathmin increases vinblastine (VLB) binding to tubulin, and that conversely VLB increases stathmin binding to tubulin. This constituted the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and revealed a new mechanism of action for VLB. The question remained if the observed interaction was specific for this drug or represented a general phenomenon for all MTAs. In the present study we investigated the binding of recombinant stathmin to purified tubulin in the presence of paclitaxel or another Vinca alkaloid, vinflunine, using Isothermal Titration Calorimetry (ITC). These experiments revealed that stathmin binding to tubulin is increased in the presence of vinflunine, whereas no signal is observed in the presence of paclitaxel. Further investigation using turbidity and co-sedimentation showed that stathmin inhibited paclitaxel microtubule-stabilizing activity. Taken together with the previous study using vinblastine, our results suggest that stathmin can be seen as a modulator of MTA activity and binding to tubulin, providing molecular explanation for multiple previous cellular and in vivo studies showing that stathmin expression level affects MTAs efficiency.
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Faculté de Pharmacie, Marseille, France.
authors.forename: Soazig
authors.initials: S
authors.lastname: Malesinski
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Faculté de Pharmacie, Marseille, France; Institute of General Pathology and Pathophysiology, RAMS, Moscow, Russian Federation.
authors.forename: Philipp O
authors.initials: PO
authors.lastname: Tsvetkov
authors.affiliation: Centre de Recherche en Oncologie Expérimentale, Centre de Recherche et Développement Pierre Fabre, Toulouse, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczynski
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Faculté de Pharmacie, Marseille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrot
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Faculté de Pharmacie, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Devred
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D002151:Calorimetry; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D012756:Sheep; D050777:Stathmin / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D050256:Antimitotic Agents; D011994:Recombinant Proteins; D050777:Stathmin; D014404:Tubulin; D050257:Tubulin Modulators; C111217:vinflunine; D014747:Vinblastine; D017239:Paclitaxel