tailieunhanh - Báo cáo khoa học: Upregulation of DR5 by proteasome inhibitors potently sensitizes glioma cells to TRAIL-induced apoptosis

This study was undertaken to explore the potential of new therapeutic approaches designed to reactivate cell death pathways in apoptosis-refrac-tory gliomas and to characterize the underlying molecular mechanisms of this reactivation. | ỊFEBS Journal Upregulation of DR5 by proteasome inhibitors potently sensitizes glioma cells to TRAIL-induced apoptosis Holger Hetschko1 Valerie Voss1 Volker Seifert1 Jochen H. M. Prehn2 and Donat Kogel1 1 Department of Neurosurgery Centre for Neurology and Neurosurgery Johann Wolfgang Goethe University Clinics Frankfurt Main Germany 2 Department of Physiology and MedicalPhysics RoyalCollege of Surgeons in Ireland Dublin Ireland Keywords apoptosis astrocytoma death receptor proteasome stress kinase Correspondence D. Kogel ExperimentalNeurosurgery Johann Wolfgang Goethe University Clinics Theodor-Stern-Kai 7 Neuroscience Centre D-60590 Frankfurt am Main Germany Fax 49 69 6301 5575 Tel 49 69 6301 6940 E-mail koegel@ Received 28 January 2008 revised 19 February 2008 accepted 21 February 2008 doi This study was undertaken to explore the potential of new therapeutic approaches designed to reactivate cell death pathways in apoptosis-refractory gliomas and to characterize the underlying molecular mechanisms of this reactivation. Here we investigated the sensitivity of a panel of glioma cell lines U87 U251 U343 U373 MZ-54 and MZ-18 to apoptosis induced by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand TRAIL TRAIL in combination with gamma irradiation and TRAIL in combination with proteasome inhibitors MG132 and epoxomicin . Analysis of these six glioma cell lines revealed drastic differences in their sensitivity to these treatments with two of the six cell lines revealing no significant induction of cell death in response to TRAIL alone. Interestingly the proteasome inhibitors MG132 and epoxomicin were capable of potentiating TRAIL-induced apoptosis in TRAIL-sensitive U87 and U251 cells and of reactivating apoptosis in TRAIL-resistant U343 and U373 cells. In contrast gamma irradiation had no synergistic effects with TRAIL in the two TRAIL-resistant cell lines. RNA interference against .