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Issue Date: 13-Feb-2012
Authors: Giunta, Salvatore
Title: Protective role of PACAP and VIP on Malignant Peripheral Nerve Sheath Tumor (MPNST) cells
Abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are often associated with poor prognosis and patient outcome. These tumors grow under conditions of metabolic stress caused by insufficient nutrients or oxygen. In our previous study we have identified PACAP, VIP and their receptors in rat MPNST cells, thus showing anti-apoptotic roles. However, the molecular mechanisms by which PACAP and VIP protect MPNST cells from death against hostile environments are still unknown. Recently it has been shown that the tumor suppressor neurofibromin, encoded by the Neurofibromatosis type I (NF1) gene, promotes MPNST cells sensitivity to apoptosis after serum withdrawal. Since tumor cells undergoing serum starvation in vitro, partially mimic nutritional deficiency conditions in vivo we evaluate how serum deprivation affected NF1 expression and establish whether PACAP or VIP negatively regulate NF1 expression. Results indicated that serum itself significantly influenced gene and protein levels. In fact, the low NF1 levels of cells cultured in normal serum-containing medium were remarkably increased in response to serum starvation. Treatment with PACAP or VIP did not affect NF1 expression when using normal amounts of serum, whereas it significantly inhibited transcript and protein levels both in low- or no-serum cultured cells. The first study provides a comprehensive analysis of both neuropeptides effect on NF1 expression in normal, low- or serum-starved MPNST cells, ameliorating the hypothesis that resistance to death against the lack of trophic support might be correlated to PACAP- / VIP-induced NF1 inhibition. In the second study we focused our research on another protein called Activity-dependent neuro-protective protein (ADNP) because converging evidence indicated that PACAP induce ADNP expression in different types of glial cells. We have investigated the involvement of this signaling system in the survival response of MPNST cells against hydrogen peroxide (H2O2)-induced cell death. Results showed that ADNP levels increased time-dependently in serum starved MPNST cells. Treatment with PACAP38 dose-dependently increased ADNP levels in the presence of normal serum but not in serum starved cells. PAC1/VPAC receptor antagonists completely suppressed PACAP-stimulated ADNP increase and partially reduced ADNP expression in serum starved cells. Normal serum cultured cells exposed to H2O2 showed significantly reduced cell viability, increased p53, caspase-3 and DNA fragmentation, without affecting ADNP expression. These effects were significantly reduced in serum starved cells and not ameliorated by PACAP38. The second study shows that ADNP induction by PACAP38 or by serum withdrawal may contribute to increase MPNST cell resistance against H2O2-induced death. In conclusion, although these evidences need further investigations to better comprehend the mechanisms involved in the protective role of these neuropetides, the common NF1 and ADNP gene induction in response to serum deprivation and the subsequent regulation induced by peptide treatments supports the hypothesis that protective action exerted by PACAP and VIP on MPNST cells might involve both NF1 and ADNP signaling.
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