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Parthenolide Inhibits Tubulin Carboxypeptidase Activity

¹ Centre de Criblage pour Molécules Bio-Actives, institut de Recherches en Technologies et Sciences pour le Vivant, Commissariat à l'Energie Atomique-Grenoble, Grenoble, France; ² Centre de Criblage Pharmacologique, Centre National de la Recherche Scientifique-Pierre Fabre Joint Service Unit #2646, Institut de Sciences et Technologies du Médicament de Toulouse; ³ Chimie des Substances Naturelles Bio-Actives, Centre National de la Recherche Scientifique-Pierre Fabre Joint Service Unit #2597, Institut de Sciences et Technologies du Médicament de Toulouse, Toulouse, France; and ⁴ Service de Marquage Moléculaire et de Chimie Bioorganique, institut de Biologie et de Technologies de Saclay, Commissariat à l'Energie Atomique-Saclay, Gif sur Yvette, France

Requests for reprints: Laurence Lafanechère, Centre de Criblage pour Molécules Bio-Actives, institut de Recherches en Technologies et Sciences pour le Vivant, Commissariat à l'Energie Atomique-Grenoble, 17 Rue des Martyrs, 38054 Grenoble, France. Phone: 33-438-78-6671; Fax: 33-438-78-5032; E-mail: laurence.lafanechere{at}cea.fr.

Microtubules are centrally involved in cell division, being the principal components of mitotic spindle. Tubulin, the constituent of microtubules, can be cyclically modified on its -subunit by enzymatic removal of the COOH-terminal tyrosine residue by an ill-defined tubulin carboxypeptidase (TCP) and its readdition by tubulin tyrosine ligase (TTL). We and others have previously shown that suppression of TTL and resulting accumulation of detyrosinated tubulin are frequent in human cancers of poor prognosis. Explanations for the involvement of TTL and detyrosinated tubulin in tumor progression arise from the recent discovery that tubulin detyrosination leads to CAP-Gly protein mislocalization, which correlates with defects in spindle positioning during mitosis. Impaired control of spindle positioning is one factor favoring tumor invasiveness. Thus, TCP could be a target for developing novel therapeutic strategies against advanced stages of cancers. Inhibitors of TCP, by reversing abnormal detyrosinated tubulin accumulation in tumor cells, could impair tumor progression. TCP has never been isolated and this has hampered search of specific inhibitors. In this article, we describe a cell-based assay of TCP activity and its use to screen a library of natural extracts for their inhibitory potency. This led to the isolation of two sesquiterpene lactones. We subsequently found that parthenolide, a structurally related compound, can efficiently inhibit TCP. This inhibitory activity is a new specific property of parthenolide independent of its action on the nuclear factor-B pathway. Parthenolide is also known for its anticancer properties. Thus, TCP inhibition could be one of the underlying mechanisms of these anticancer properties. [Cancer Res 2007;67(7):3371–8]