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 A-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-KB pathway. Parthenolide is also known for its anticancer properties. Thus, TCP inhibition could be one of the underlying mechanisms of these anticancer properties.

Nuclear factor-κB inhibition provides additional protection against ischaemia/reperfusion injury in delayed sevoflurane preconditioning

“…As parth was given immediately before I/R, and on the basis of the results of prior studies and the results of our experiments, we believe that the effect of parth was both lasting and substantial [43]. Although parth is recognized as an IkB kinase complex inhibitor [28], recent studies [44,45] suggest that parth could affect other pathways without inhibiting NF-kB. Finally, another control group, that of SPC þ vehicle given 48 h prior to I/R, was not included as the vehicle used in this study has not shown any protective effects in prior studies [28,46].…”

The role of oxidative stress in anticancer activity of sesquiterpene lactones

“…PTL decreases also the activity of histone deacetylase (HDAC) (Gopal et al 2007) and DNA methyltranspherase 1 (DNMT1) (Liu et al 2009). Furthermore, PTL can interfere with microtubule function through tubulin binding (Fonrose et al 2007). However, the main mechanism of PTL action is linked to the inhibition of NF-κB (Rüngeler et al 1999).…”

Parthenolide, a Sesquiterpene Lactone, Expresses Multiple Anti-cancer and Anti-inflammatory Activities

“…Studies have shown that parthenolide actively interferes with microtubule formation [47] by reducing impaired control of spindle positioning. As spindle positioning is a factor favoring tumor invasiveness in cancer cells [47,48], microtubles may be a good target for cancer therapy. Chemical agents that primarily target cell cycle machinery are assumed to be potent anti-cancer drugs [48,49].…”