Glioblastoma multiforme (GBM), a grade-IV glioma, is resistant to TNF-α induced apoptosis. CLIPR-59 modulates ubiquitination of RIP1, thus promoting Caspase-8 activation to induce apoptosis by TNF-α. Here we reported that CLIPR-59 was down-regulated in GBM cells and high-grade glioma tumor samples, which was associated with decreased cancer-free survival. In GBM cells, CLIPR-59 interacts with Spy1, resulting in its decreased association with CYLD, a de-ubiquitinating enzyme. Moreover, experimental reduction of Spy1 levels decreased GBM cells viability, while increased the lysine-63-dependent de-ubiquitinating activity of RIP1 via enhancing the binding ability of CLIPR-59 and CYLD in GBM, thus promoting Caspase-8 and Caspase-3 activation to induce apoptosis by TNF-α. These findings have identified a novel Spy1-CLIPR-59 interplay in GBM cell's resistance to TNF-α-induced apoptosis revealing a potential target in the intervention of malignant brain tumors.
Keywords: CLIPR-59; CLIPR-59, CLIP-170-related 59 kDa protein; FADD, Fas-associated protein with death domain; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GBM glioblastoma multiforme; Glioma; RIP1; RIP1, receptor-interacting protein 1; Spy1; Spy1, speedy inducer of meiotic maturation; TNF-α; TNFR1, TNF-receptor-type 1; TRADD, TNF receptor-associated death domain protein; apoptosis.