RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma

• DOI: 10.1007/s13277-015-4621-6
• Publication Date: 2015-12-18T01:17:15Z
• Authors: Arabinda Das; Daniel G. McDonald; Yaenette N. Dixon...; Dustin J. Jacqmin; Vikram N. Samant; William A. Vander...; Scott M. Lindhorst; David Cachia; Abhay K. Varma; Kenneth N. Vanek; Naren L. Banik; Joseph M. Jenrette; Jeffery J. Raizer; Pierre Giglio; Sunil J. Patel
• Keywords: Intrinsic apoptosis

Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and ways RN differ from regulated cell death (apoptosis) are not well understood. Here, we compare mechanism (apoptosis or necrosis) C6 glioma cells in both vitro vivo (C6 othotopically allograft) models response to low high doses X-ray radiation. Lower were used induce apoptosis, while high-dose levels chosen necrosis. Our results demonstrate that active caspase-8 this complex I induces apoptosis low-dose inhibits by cleaving RIP1 RI. When activation was reduced at radiation, RIP1/RIP3 necrosome II formed. These complexes through caspase-3-independent pathway mediated calpain, cathepsin B/D, apoptosis-inducing factor (AIF). AIF has dual role At doses, promotes chromatinolysis interacting with histone H2AX. In addition, NF-κB, STAT-3, HIF-1 play crucial radiation-induced inflammatory responses embedded network. Analysis markers matched plasma cerebrospinal fluid (CSF) isolated specimens demonstrated upregulation chemokines cytokines during phase. Using kinase specific inhibitors (Nec-1, GSK'872), also establish RIP1-RIP3 regulates programmed after either TNF-α-induced requires RIP3 kinases. Overall, our data shed new light on relationship between RIP1/RIP3-mediated AIF-mediated caspase-independent