PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-κB Activation

• Published in: Molecular cancer research 2009-04, Vol.7 (4), p.557-569
• Main Authors: Tanaka, Hiroshi, Hoshikawa, Yutaka, Oh-hara, Tomoko, Koike, Sumie, Naito, Mikihiko, Noda, Tetsuo, Arai, Hiroyuki, Tsuruo, Takashi, Fujita, Naoya
• Format: Article
• Language: English
• Subjects: DR4; DR5; IKK; NF-κB; protein arginine methyltransferase
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-08-0197

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and has selective antitumor activity. Although TNF-α-induced intracellular signaling pathways have been well studied, TRAIL signaling is not fully understood. Here, we identified a novel TRAIL receptor-binding protein, protein arginine methyltransferase 5 (PRMT5), as a result of proteomic screening. PRMT5 selectively interacted with death receptor 4 and death receptor 5 but not with TNF receptor 1 or Fas. PRMT5 gene silencing sensitized various cancer cells to TRAIL without affecting TRAIL resistance in nontransformed cells. PRMT5 contributed to TRAIL-induced activation of inhibitor of κB kinase (IKK) and nuclear factor-κB (NF-κB), leading to induction of several NF-κB target genes. Although IKK inhibition increased sensitivity to both TRAIL and TNF-α, PRMT5 knockdown potentiated TRAIL-mediated cytotoxicity alone. PRMT5 had no effect on TNF-α-mediated NF-κB signaling. These results show the selectivity of PRMT5 for TRAIL signaling. The PRMT5 small interfering RNA-mediated susceptibility to TRAIL was rescued by ectopic expression of active IKKβ, confirming the involvement of PRMT5 in TRAIL resistance by activating the NF-κB pathway. Collectively, our findings suggest the therapeutic potential of PRMT5 in TRAIL-based cancer treatments.(Mol Cancer Res 2009;7(4):557–69)