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Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy
Artesi, Maria; Kroonen, Jerome; Bredel, Markus et al.
2015In Neuro-Oncology
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Keywords :
connexin 30; glioblastoma; mitochondria; proliferation; radiation resistance
Abstract :
[en] Connexins (Cxs) are potentially key players in the control of tumor cell proliferation. Normal astrocytes express large amounts of connexin30 and we have previously demonstrated its underexpression in rat glioma cells. Here we report that a Cx30 gene deletion occurs in approximately 30% of human glioblastomas (GBMs). Cx30 mRNA levels are decreased in these tumors compared to glial tumors of lower grade and to non tumoral tissues. At the protein level, Cx30 is lost in approximately one third of the tumors in our cohort of 230 glioblastoma biopsies. Restoration of Cx30 in U87 glioma cell lines and in glioma primary cultures (GM1), effectively retards cell proliferation in vitro and inhibits tumor growth in vivo. This correlates with a decrease in TCF, CK2 and NFkappaB activity and with altered expression levels of cell cycle control proteins such as cyclin D1, P27, P21 and c-myc. In patient biopsies, Cx30 expression was found in tumor regions displaying a lower Ki-67 proliferative index. Interestingly, in our cohort of malignant glioma patients, Cx30 expression proved to be an adverse prognostic factor. Here, we demonstrate its role in mediating cell survival and a hypermetabolic state after radiation treatment in human glioma cells. Mechanistically, we propose that a HSP90- mediated Cx30 translocation into mitochondria occurs after radiation treatment. The inhibition of the HSP90 molecular chaperone with geldamycin inhibits the radiation- induced translocation of Cx30 into mitochondria, decreasing the hypermetabolic state and restoring radiation sensitivity in those cells. These results demonstrate the central regulatory role of connexin30 in the biology of human gliomas.
Disciplines :
Oncology
Genetics & genetic processes
Author, co-author :
Artesi, Maria ;  Université de Liège > GIGA-Research
Kroonen, Jerome
Bredel, Markus
Nguyen-Khac, Minh
Deprez, Manuel
SCHOYSMAN, Laurent ;  Centre Hospitalier Universitaire de Liège - CHU > Service médical de radiodiagnostic
Poulet, Christophe  ;  Université de Liège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine
Chakravarti, Arnab
Kim, Hyunsoo
Scholtens, Denise
Seute, Tatjana
ROGISTER, Bernard  ;  Centre Hospitalier Universitaire de Liège - CHU > Service de neurologie
BOURS, Vincent ;  Centre Hospitalier Universitaire de Liège - CHU > Service de génétique
Robe, Pierre ;  Université de Liège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
More authors (4 more) Less
Language :
English
Title :
Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy
Publication date :
2015
Event name :
4th quadriennal meeting of the world federation of neuro-oncology
Event place :
San Francisco, United States - California
Event date :
21-24 November 2103
Audience :
International
Journal title :
Neuro-Oncology
ISSN :
1522-8517
eISSN :
1523-5866
Publisher :
Oxford University Press
Peer reviewed :
Peer Reviewed verified by ORBi
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