Parthenolide inhibits tubulin carboxypeptidase activity

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 (TC...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2007-04, Vol.67 (7), p.3371-3378
Hauptverfasser: FONROSE, Xavier, AUSSEIL, Frédéric, LAFANECHERE, Laurence, SOLEILHAC, Emmanuelle, MASSON, Veronique, DAVID, Bruno, POUNY, Isabelle, CINTRAT, Jean-Christophe, ROUSSEAU, Bernard, BARETTE, Caroline, MASSIOT, Georges
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container_end_page 3378
container_issue 7
container_start_page 3371
container_title Cancer research (Chicago, Ill.)
container_volume 67
creator FONROSE, Xavier
AUSSEIL, Frédéric
LAFANECHERE, Laurence
SOLEILHAC, Emmanuelle
MASSON, Veronique
DAVID, Bruno
POUNY, Isabelle
CINTRAT, Jean-Christophe
ROUSSEAU, Bernard
BARETTE, Caroline
MASSIOT, Georges
description 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.
doi_str_mv 10.1158/0008-5472.CAN-06-3732
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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. 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subjects Antineoplastic agents
Biological and medical sciences
Cancer
Carboxypeptidases - antagonists & inhibitors
Carboxypeptidases - metabolism
Cellular Biology
Drug Interactions
HeLa Cells
Humans
Life Sciences
Medical sciences
NF-kappa B - antagonists & inhibitors
Paclitaxel - pharmacology
Pharmacology. Drug treatments
Sesquiterpenes - chemistry
Sesquiterpenes - pharmacology
Structure-Activity Relationship
Tubulin - metabolism
Tumors
title Parthenolide inhibits tubulin carboxypeptidase activity
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