Abstract 4008: p75NTR is overexpressed in vestibular schwannomas and protects cells from apoptosis due to suppressed c-Jun N-terminal kinase (JNK) activity

Abstract

Abstract Vestibular schwannomas (VSs) represent benign Schwann cell (SC) neoplasms arising from the eighth cranial nerve and account for 8-10% of all intracranial neoplasms. Denervation by axotomy leads to increased p75NTR expression, JNK activation, and eventual death of SCs. In contrast to SCs, VS cells survive in the absence of axons and here we investigated the interactions of p75NTR and JNK signaling on the survival response of cultured primary human VS cells. Using qRT-PCR and western blotting, we find that p75NTR is over-expressed in VS cells compared with normal nerve. However, in contrast to normal SCs, treatment of cultured VS cells with pro-NGF, a high affinity ligand for p75NTR, failed to induce apoptosis. We confirmed that VS cells express sortilin, a co-receptor with p75NTR to bind pro-NGF and induce apoptosis. We further show that VS cells display persistent JNK phosphorylation and activity compared with normal SCs. Treatment of VS cultures with the JNK inhibitors, I-JIP or SP600125, results in decreased proliferation, increased apoptosis, and increased accumulation of mitochondrial superoxides. Overexpression of mitochondrial superoxide dismutase prevents apoptosis due to suppressed JNK. These results suggest that persistent JNK contributes to the survival of VS cells, at least in part, by suppressing accumulation of mitochondrial superoxides. Treatment of VS cultures with proNGF protected the cells from apoptosis due to JNK inhibition. This protective effect is specific to proNGF and not seen with other neural derived growth factors such as neuregulin-1 (NRG-1). Indeed treatment with NRG-1 increased apoptosis in cultures with suppressed JNK activity. Further, VS cells lack Trk expression supporting the notion that the protective effect of proNGF is mediated by p75NTR. These results suggest that, in contrast to normal SCs which undergo apoptosis in response to p75NTR and JNK signaling, these signals promote VS cell survival. Such differences may account for the ability of VS cells to proliferate and survive in the absence of axons. Support: DOD NF050193 and NIDCD R01DC009801 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4008.