Goat anti Rat NGF polyclonal antibody

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.

Neurotrophins are a family of growth factors crucial for growth and survival of neurons in the developing and adult brain. Reduction in neurotrophin levels is associated with reduced neurogenesis and cognitive deficits in rodents. Recently, we demonstrated that long-term exposure to low levels of the pyrethroid pesticide deltamethrin causes hippocampal endoplasmic reticulum (ER) stress and learning deficits in mice. Here, we found that nerve growth factor (NGF) mRNA and protein were selectively reduced in the hippocampus of deltamethrin-treated mice. To explore potential mechanisms responsible for this observation, we employed mouse primary hippocampal neurons. Exposure of neurons to deltamethrin (1-5 mu M) caused ER stress as indicated by increased levels of C/EBP-homologous protein (CHOP) and glucose-regulated protein 78 (GRP78). These changes were accompanied by increased levels of caspase-12, activated caspase-3, and decreased levels of NGF. Inhibition of ER stress with the eukaryotic initiation factor 2 alpha (eIF2 alpha) inhibitor salubrinal abolished deltamethrin-induced activation of caspase-12 and caspase-3, and restored NGF levels. Furthermore, deltamethrin decreased Akt (protein kinase B) phosphorylation, which was significantly prevented by co-treatment with NGF or SC-79 in cells. Collectively, these results demonstrate that the loss of NGF following ER stress may contribute to deltamethrin-induced apoptosis in the hippocampus through the Akt signaling pathway, and that this may provide a plausible mechanism for impaired learning and memory observed following exposure of mice to deltamethrin.