Authors: HeeYoung Jeon JunKyum Kim Seok Won Ham SeYeong Oh Jaebong Kim JaeBong Park JaeYong Lee SungChan Kim Hyunggee Kim
Publish Date: 2015/11/19
Volume: 37, Issue: 5, Pages: 5857-5867
Abstract
Glioblastoma multiforme GBM is one of the most aggressive and fatal primary brain tumors in humans The standard therapy for the treatment of GBM is surgical resection followed by radiotherapy and/or chemotherapy However the frequency of tumor recurrence in GBM patients is very high and the survival rate remains poor Delineating the mechanisms of GBM recurrence is essential for therapeutic advances Here we demonstrate that irradiation rendered 17–20 of GBM cells dead but resulted in 60–80 of GBM cells growtharrested with increases in senescence markers such as senescenceassociated betagalactosidasepositive cells H3K9me3positive cells and p53p21CIP1positive cells Moreover irradiation induced expression of senescenceassociated secretory phenotype SASP mRNAs and NFκB transcriptional activity in GBM cells Strikingly compared to injection of nonirradiated GBM cells into immunedeficient mice the coinjection of irradiated and nonirradiated GBM cells resulted in faster growth of tumors with the histological features of human GBM Taken together our findings suggest that the increases in senescent cells and SASP in GBM cells after irradiation is likely one of main reasons for tumor recurrence in postradiotherapy GBM patientsWe would like to thank all the members of the Cell Growth Regulation Laboratory for their helpful discussion and technical assistance This work was supported by the National Nuclear Technology Program through the National Research Foundation NRF of Korea funded by the Ministry of Science ICT and Future Planning No 2013M2A2A7042530 to H Kim and a research grant to SY Oh funded by the Institute of Life Science and Natural Resources at Korea UniversityIrradiationinduced GBM cell death was decreased by inhibition of NFκB signaling FACS analysis revealed that early apoptotic cell populations Annexin Vpositive/PInegative of IκBα mutantexpressing GBM cells U87MG and LN229 decreased compared to control counterpart GBM cells on Day 3 after irradiation with 20 Gy There was no obvious difference on necrotic cell population Annexin Vnegative/PIpositive in these cells GIF 105 kbIrradiated GBM cells are not present in the tumor xenograft a FACS analysis showed cell populations expressing DsRed fluorescence in the mix of nonirradiated LN229 1 × 10 and irradiated DsRedexpressing LN229 cells 2 × 10 before in vivo mouse coinjection This experiment was set for a positive control b FACS analysis revealed that DsRedpositive cell populations were not present in tumors derived from the mix of nonirradiated LN229 and irradiated DsRedexpressing LN229 cells Single cells dissociated from tumors derived from nonirradiated LN229 cells alone were used as a negative control GIF 133 kb
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