Neudesin, a novel secreted protein with a unique primary structure and neurotrophic activity

Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and increase metabolism. Progesterone receptor membrane component 1 (Pgrmc1) is related to cytochrome b 5 , binds to heme, and is associated with DNA damage resistance and apoptotic suppression. Pgrmc1 is induced by carcinogens, including dioxin, and is up-regulated in multiple types of cancer. In the present study, we found that Pgrmc1 increased in vivo tumor growth, anchorage-independent growth, and migration. Pgrmc1 also promoted proliferation in the absence of serum in A549 non-small cell lung cancer cells but enhanced proliferation regardless of serum concentration in MDA-MB-468 breast cancer cells. Pgrmc1 promotes cholesterol synthesis and binds to Insig (insulininduced gene), Scap (sterol regulatory element binding protein cleavage activating protein), and P450 proteins, but Pgrmc1 did not affect cholesterol synthesis in lung cancer cells. Pgrmc1 is also associated with progesterone signaling and plasminogen activator inhibitor (PAI1) RNA binding protein, but neither progesterone activity nor PAI1 transcript levels were altered in Pgrmc1-knockdown lung cancer cells. Pgrmc1 homologues bind to aryl ligands identified in an in silico screen, and we have found that a Pgrmc1 ligand induced cell death in a Pgrmc1-specific manner in multiple breast and lung tumor cell lines. Our data support a role for Pgrmc1 in promoting cancer-associated phenotypes and provide a therapeutic approach for targeting Pgrmc1 with a small molecule in lung and breast cancer.

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“…4C) (Kimura et al, 2005(Kimura et al, , 2008. In Pgrmc1-knockdown cells, Pgrmc2 transcription increased (Fig.…”

Section: Discussionmentioning

confidence: 84%

Progesterone Receptor Membrane Component 1 (Pgrmc1): A Heme-1 Domain Protein That Promotes Tumorigenesis and Is Inhibited by a Small Molecule

Ahmed

Rohe²,

Twist³

et al. 2010

J Pharmacol Exp Ther

133

149

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“…Knockdown of RASAL2 decreases ECT2 activity toward RHO in astrocytoma cells and leads to mesenchymal-amoeboid transition, altering the invasive properties of the cells. NENF is a secreted protein with neurotrophic activity expressed abundantly in the developing brain and spinal cord (15). It was shown to induce phosphorylation of ERK1/2 and AKT in primary cultured mouse neurons and MCF-7 breast cancer cells (15).…”

Section: Introductionmentioning

confidence: 99%

“…NENF is a secreted protein with neurotrophic activity expressed abundantly in the developing brain and spinal cord (15). It was shown to induce phosphorylation of ERK1/2 and AKT in primary cultured mouse neurons and MCF-7 breast cancer cells (15). NENF is also highly expressed in several cancers and its overexpression in MCF-7 breast cancer cells increases their tumorigenicity and invasiveness (16).…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Study of Hypomethylated and Induced Genes in Patients with Liver Cancer Unravels Novel Anticancer Targets

Stefańska

Cheishvili

Suderman

et al. 2014

Clinical Cancer Research

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Purpose: We utilized whole-genome mapping of promoters that are activated by DNA hypomethylation in hepatocellular carcinoma (HCC) clinical samples to shortlist novel targets for anticancer therapeutics. We provide a proof of principle of this approach by testing six genes short-listed in our screen for their essential role in cancer growth and invasiveness.Experimental Design: We used siRNA-or shRNA-mediated depletion to determine whether inhibition of these genes would reduce human tumor xenograft growth in mice as well as cell viability, anchorageindependent growth, invasive capacities, and state of activity of nodal signaling pathways in liver, breast, and bladder cancer cell lines.Results: Depletion of EXOSC4, RNMT, SENP6, WBSCR22, RASAL2, and NENF effectively and specifically inhibits cancer cell growth and cell invasive capacities in different types of cancer, but, remarkably, there is no effect on normal cell growth, suggesting a ubiquitous causal role for these genes in driving cancer growth and metastasis. Depletion of RASAL2 and NENF in vitro reduces their growth as explants in vivo in mice. RASAL2 and NENF depletion interferes with AKT, WNT, and MAPK signaling pathways as well as regulation of epigenetic proteins that were previously demonstrated to drive cancer growth and metastasis.Conclusion: Our results prove that genes that are hypomethylated and induced in tumors are candidate targets for anticancer therapeutics in multiple cancer cell types. Because these genes are particularly activated in cancer, they constitute a group of targets for specific pharmacologic inhibitors of cancer and cancer metastasis. Clin Cancer Res; 20(12); 3118-32. Ó2014 AACR.

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“…We demonstrated that hypothalamic signaling pathways in the mouse respond to the human NENF protein. Physiological processes activated by NENF signaling may be evolutionarily conserved since the human and mouse proteins have 91% similarity (31), which suggests that NENF may be a novel candidate biomarker for disease susceptibility or development of novel drug therapeutics in humans.…”

Section: Perspectives and Significancementioning

confidence: 99%

“…Several characteristics prompted us to select one candidate protein from this screen for in-depth characterization, neuron-derived neurotrophic factor (Nenf or neudesin). Mouse Nenf contains 171 amino acids, is 91% similar to human NENF, is primarily expressed in neurons, but is absent from glia (31). In addition, it is expressed in white adipose tissue (28).…”

mentioning

confidence: 99%

Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite

Byerly

Swanson

Semsarzadeh

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Byerly MS, Swanson RD, Semsarzadeh NN, McCulloh PS, Kwon K, Aja S, Moran TH, Wong GW, Blackshaw S. Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite. Am J Physiol Regul Integr Comp Physiol 304: R1085-R1095, 2013. First published April 10, 2013 doi:10.1152/ajpregu.00368.2012.-Disruption of finely coordinated neuropeptide signals in the hypothalamus can result in altered food intake and body weight. We identified neuron-derived neurotrophic factor (NENF) as a novel secreted protein through a large-scale screen aimed at identifying novel secreted hypothalamic proteins that regulate food intake. We observed robust Nenf expression in hypothalamic nuclei known to regulate food intake, and its expression was altered under the diet-induced obese (DIO) condition relative to the fed state. Hypothalamic Nenf mRNA was regulated by brain-derived neurotrophic factor (BDNF) signaling, itself an important regulator of appetite. Delivery of purified recombinant BDNF into the lateral cerebral ventricle decreased hypothalamic Nenf expression, while pharmacological inhibition of trkB signaling increased Nenf mRNA expression. Furthermore, recombinant NENF administered via an intracerebroventricular cannula decreased food intake and body weight and increased hypothalamic Pomc and Mc4r mRNA expression. Importantly, the appetite-suppressing effect of NENF was abrogated in obese mice fed a high-fat diet, demonstrating a diet-dependent modulation of NENF function. We propose the existence of a regulatory circuit involving BDNF, NENF, and melanocortin signaling. Our study validates the power of using an integrated experimental and bioinformatic approach to identify novel CNS-derived proteins with appetite-modulating function and reveals NENF as an important central modulator of food intake.brain-derived neurotrophic factor; melanocortin; whole-body energy balance; neural circuitry; agouti-related protein ENERGY HOMEOSTASIS INVOLVES finely tuned coordination of signals arising from both peripheral sources and the central nervous system (CNS) to establish a well-balanced homeostatic feedback loop. Hypothalamic neuropeptides and other secreted proteins play a critical role in modulating body weight and food intake. Lesions of the lateral nuclei of the hypothalamus result in anorexia, and while lesions of both the ventromedial (VMH) or paraventricular nuclei (PVN) result in excessive food intake and body weight gain (3,22). Further, disruption of hypothalamic neuropeptide signals (e.g., brain-derived neurotrophic factor, BDNF; Agoutirelated protein, AGRP) in loss-of-function mouse models can lead to metabolic diseases and obesity (48, 63).Neurotrophic factors act as neuromodulators to maintain growth, survival, and differentiation of neurons (24, 49). Genetic evidence implicates the BDNF signaling pathway in regulating feeding and body weight. A missense mutation in the BDNF receptor, tyrosine kinase receptor B (TRKB), has been identified in severely obese children (19, 59). Additionally...

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Neudesin, a novel secreted protein with a unique primary structure and neurotrophic activity

Cited by 59 publications

References 25 publications

Progesterone Receptor Membrane Component 1 (Pgrmc1): A Heme-1 Domain Protein That Promotes Tumorigenesis and Is Inhibited by a Small Molecule

Progesterone Receptor Membrane Component 1 (Pgrmc1): A Heme-1 Domain Protein That Promotes Tumorigenesis and Is Inhibited by a Small Molecule

Genome-Wide Study of Hypomethylated and Induced Genes in Patients with Liver Cancer Unravels Novel Anticancer Targets

Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite

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