title: Parthenolide inhibits tubulin carboxypeptidase activity.
abstract: 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 alpha-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-kappaB pathway. Parthenolide is also known for its anticancer properties. Thus, TCP inhibition could be one of the underlying mechanisms of these anticancer properties.
authors.affiliation: 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fonrose
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ausseil
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Soleilhac
authors.forename: Véronique
authors.initials: V
authors.lastname: Masson
authors.forename: Bruno
authors.initials: B
authors.lastname: David
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pouny
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cintrat
authors.forename: Bernard
authors.initials: B
authors.lastname: Rousseau
authors.forename: Caroline
authors.initials: C
authors.lastname: Barette
authors.forename: Georges
authors.initials: G
authors.lastname: Massiot
authors.forename: Laurence
authors.initials: L
authors.lastname: Lafanechère
mesh_terms: D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004347:Drug Interactions; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017239:Paclitaxel / Q000494:pharmacology; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012717:Sesquiterpenes; D014404:Tubulin; C002669:parthenolide; D002268:Carboxypeptidases; C023212:tyrosyltubulin carboxypeptidase; D017239:Paclitaxel