Down-Regulation of PER2 Increases Apoptosis of Gliomas after X-Ray Irradiation

Abstract

Period2 (PER2), a core circadian gene, not only modulates circadian rhythm but also may play an important role in other biological processes including pathways involved in the proliferation and apoptosis of tumor cells. In this study, we investigated the mechanism by which downregulated expression of PER2 promotes apoptosis of wild-type TP53 human glioma U343 cells exposed to X-rays. U343 cells were irradiated with 6mV 10Gy X-ray irradiation after infection with shRNA lentivirus to reduce expression of PER2, and then analyzed by several methods such as SCGE analysis, flow cytometry, RT-PCR, and western blotting. Compared with controls, U343 cells expressing low levels of PER2 showed serious DNA damage when exposed to X-ray irradiation in SCGE analysis (P<0.05), and higher death rates in flow cytometry assay (P<0.05). RT-PCR and western blot analysis both revealed decreased expression of ATM and TP53, which regulate DNA damage and repair via the ATM-TP53 pathway, and an increased expression of C-MYC, which is related to cell apoptosis. Thus, our research suggests that PER2 may play an important role in tumor radiotherapy, which is attributable to enhanced ATM-TP53 signaling and pro-apoptotic processes. These findings provide a new target for the clinical treatment of glioma, and a reliable basis for postradiation therapy and gene therapy for glioma and other cancers.

Insights About Circadian Clock and Molecular Pathogenesis in Gliomas

“…The results were ascribed to the reduced expression of ataxia telangiectasia mutated (ATM) and TP53encoding genes, which regulate DNA damage and repair via the ATM-TP53 pathway. Increased expression of c-Myc was correlated to the apoptotic activity (104).…”