RADIOBIOLOGY

Le résumé fourni par la source

Connexins appear as key players in the control of tumor cell proliferation.Normal astrocytes express the transmembrane protein connexin30, but we report here that a Cx30 gene (GJB6) deletion occurs in approximately 30% of human glioblastomas and that Cx30 protein expression is lost in approximately one third of the tumors in a personal cohort of 230 glioblastoma samples.Restoration of Cx30 in U87 glioma cell lines and in glioma primary cultures, effectively retards cell proliferation in vitro and inhibits tumor growth in vivo.This correlates with a decrease in TCF, CK2 and NFkappaB activity and reduced expression 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.In contrast however, in our cohort of malignant glioma patients as well as in a second, independent cohort, Cx30 expression inversely correlated with survival.Here, we demonstrate its role in mediating cell survival and a hypermetabolic state after radiation treatment in human glioma cells.Mechanistically, a HSP90-dependent translocation of Cx30 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 dual regulatory role of connexin30 in the biology of human gliomas, as a suppressor of tumor growth and a radioresistance protein, and single it out as a potential target for therapeutic interventions against these tumors.

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