Involvement of PACAP/ADNP Signaling in the Resistance to Cell Death in Malignant Peripheral Nerve Sheath Tumor (MPNST) Cells

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas able to grow under conditions of metabolic stress caused by insufficient nutrients or oxygen. Both pituitary adenylate cyclase-activating polypeptide (PACAP) and activity-dependent neuroprotective protein (ADNP) have glioprotective potential. However, whether PACAP/ADNP signaling is involved in the resistance to cell death in MPNST cells remains to be clarified. Here, we investigated the involvement of this signaling system in the survival response of MPNST cells against hydrogen peroxide (H(2)O(2))-evoked death both in the presence of normal serum (NS) and in serum-starved (SS) cells. Results showed that ADNP levels increased time-dependently (6-48 h) in SS cells. Treatment with PACAP38 (10(-9) to 10(-5) M) dose-dependently increased ADNP levels in NS but not in SS cells. PAC(1)/VPAC receptor antagonists completely suppressed PACAP-stimulated ADNP increase and partially reduced ADNP expression in SS cells. NS-cultured cells exposed to H(2)O(2) showed significantly reduced cell viability (~50 %), increased p53 and caspase-3, and DNA fragmentation, without affecting ADNP expression. Serum starvation significantly reduced H(2)O(2)-induced detrimental effects in MPNST cells, which were not further ameliorated by PACAP38. Altogether, these finding provide evidence for the involvement of an endogenous PACAP-mediated ADNP signaling system that increases MPNST cell resistance to H(2)O(2)-induced death upon serum starvation.

PACAP and VIP increase the expression of myelin-related proteins in rat schwannoma cells: Involvement of PAC1/VPAC2 receptor-mediated activation of PI3K/Akt signaling pathways

“…In this regard, previous works have proposed that the axon-cell contact independent ability of Schwann cells to switch from a non-myelinating to a myelinating state in vitro may partly depend on their differentiation state, which can be triggered by serum withdrawal [30,9]. In line with these evidences, we have previously found that the RT4 schwannoma cell line used in the present study behaved similarly to primary Schwann cells when starved from serum, acquiring a more differentiated-like phenotype [7]. Furthermore, when starved for short periods, RT4 schwannoma cells showed increased endogenous expression of PACAP and related receptors both at mRNA [7] and protein levels, as observed in the present study ( Fig.…”

“…3C), while both PAC1 and VPAC2 expression levels were augmented by about 1.7-folds in SS cells (t 4 ¼4.656 and t 4 ¼ 2.795, p¼ 0.0096 and p¼ 0.049 vs. Ctrl, respectively). These results, together with previous evidences [7], suggest that a short period of serum withdrawal might be sufficient to trigger the activation of the endogenous PACAP/VIP signaling system, possibly through an autocrine/paracrine loop.…”

“…In a recent study we have demonstrated that serum starvation renders RT4-P6D2T cells resilient to oxidative insults, possibly by inducing endogenous activation of PACAP/VPAC2 signaling [7]. These evidences suggested that growth factor withdrawal might be determinant to trigger significant adaptive changes in this cell line.…”

“…In the CNS, they act as neurotransmitters and neuromodulators, but are also involved in regulating processes such as cell division, neuronal differentiation, embryonic development, and neuronal survival [14,35,37]. In the PNS, they exert both neuro-and glio-protective actions against various type of insults [8,7,13], and endogenous peptides have been shown to mediate pro-regenerating effects after peripheral nerve injuries in vivo, where overexpression is observed at the level of the injury site [31]. From another study it has emerged that local administration of VIP accelerates early myelination and growth of regenerating axons after sciatic nerve transection [39].…”

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

“…ADNP interacts with components of the BAF complex, the eukaryotic equivalent of the SWI/SNF complex in yeast, which is involved in the regulation of gene expression (34). In cancer cells, ADNP regulates cell growth and differentiation and, under stress conditions, exhibits expression changes leading to cancer progression (35). In contrast, in intestinal cancer cells, downregulation of ADNP by antisense oligodeoxynucleotides upregulates the TS p53 and reduces the viability of intestinal cancer cells (36).…”