Another Facet to the Anticancer Response ...
Document type :
Article dans une revue scientifique
DOI :
PMID :
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Title :
Another Facet to the Anticancer Response to Lamellarin D: Induction of Cellular Senescence through Inhibition of Topoisomerase I and Intracellular Ros Production
Author(s) :
Ballot, Caroline [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Martoriati, Alain [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Jendoubi, Manel [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Buche, Sébastien [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Formstecher, Pierre [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Mortier, Laurent [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Kluza, Jerome [Auteur]
Marchetti, Philippe [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Martoriati, Alain [Auteur]

Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Jendoubi, Manel [Auteur]

Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Buche, Sébastien [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Formstecher, Pierre [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Mortier, Laurent [Auteur]

Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Kluza, Jerome [Auteur]

Marchetti, Philippe [Auteur]

Journal title :
Marine Drugs
Volume number :
12
Pages :
779-798
Publication date :
2014-01-27
ISSN :
1660-3397
English keyword(s) :
oxidative stress response
mitochondria
DNA damage
cellular senescence
mitochondria
DNA damage
cellular senescence
HAL domain(s) :
Chimie/Chimie théorique et/ou physique
English abstract : [en]
Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities. Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear ...
Show more >Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities. Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear topoisomerase I, relevant kinases (such as cyclin-dependent kinase 2) and the mitochondrial electron transport chain. While we have previously demonstrated that LamD at micromolar range deploys strong cytotoxicity by inducing mitochondrial apoptosis, mechanisms of its cytostatic effect have not yet been characterized. Here, we demonstrated that induction of cellular senescence (depicted by cell cycle arrest in G2 associated with β-galactosidase activity) is a common response to subtoxic concentrations of LamD. Cellular senescence is observed in a large panel of cancer cells following in vitro or in vivo exposure to LamD. The onset of cellular senescence is dependent on the presence of intact topoisomerase I since topoisomerase I-mutated cells are resistant to senescence induced by LamD. LamD-induced senescence occurs without important loss of telomere integrity. Instead, incubation with LamD results in the production of intracellular reactive oxygen species (ROS), which are critical for senescence as demonstrated by the inhibitory effect of antioxidants. In addition, cancer cells lacking mitochondrial DNA also exhibit cellular senescence upon LamD exposure indicating that LamD can trigger senescence, unlike apoptosis, in the absence of functional mitochondria. Overall, our results identify senescence-associated growth arrest as a powerful effect of LamD and add compelling evidence for the pharmacological interest of lamellarins as potential anticancer agents.Show less >
Show more >Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities. Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear topoisomerase I, relevant kinases (such as cyclin-dependent kinase 2) and the mitochondrial electron transport chain. While we have previously demonstrated that LamD at micromolar range deploys strong cytotoxicity by inducing mitochondrial apoptosis, mechanisms of its cytostatic effect have not yet been characterized. Here, we demonstrated that induction of cellular senescence (depicted by cell cycle arrest in G2 associated with β-galactosidase activity) is a common response to subtoxic concentrations of LamD. Cellular senescence is observed in a large panel of cancer cells following in vitro or in vivo exposure to LamD. The onset of cellular senescence is dependent on the presence of intact topoisomerase I since topoisomerase I-mutated cells are resistant to senescence induced by LamD. LamD-induced senescence occurs without important loss of telomere integrity. Instead, incubation with LamD results in the production of intracellular reactive oxygen species (ROS), which are critical for senescence as demonstrated by the inhibitory effect of antioxidants. In addition, cancer cells lacking mitochondrial DNA also exhibit cellular senescence upon LamD exposure indicating that LamD can trigger senescence, unlike apoptosis, in the absence of functional mitochondria. Overall, our results identify senescence-associated growth arrest as a powerful effect of LamD and add compelling evidence for the pharmacological interest of lamellarins as potential anticancer agents.Show less >
Language :
Anglais
Audience :
Non spécifiée
Administrative institution(s) :
CHU Lille
CNRS
Inserm
Université de Lille
CNRS
Inserm
Université de Lille
Collections :
Research team(s) :
Régulation des signaux de division
Submission date :
2020-02-12T15:44:32Z
2021-03-12T14:08:53Z
2021-03-12T14:08:53Z
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