Nerve growth factor (NGF) receptors, TrKA and p75(NTR), are being investigated in cancer therapy. Our previous data show that, in HTB114 uterine leiomyosarcoma cells, p75(NTR)-dependent apoptosis is inducible by cytotoxic drugs and can suppress nerve growth factor-dependent growth. Although amitriptyline can kill cancer cells and bind TrKA/B, its effects on p75-dependent apoptosis are unknown. The aim of this paper was to evaluate the antineoplastic potential of amitriptyline, and the role of p75(NTR)-dependent apoptosis in the chemoresistant uterine HTB114 leiomyosarcoma. Using proliferation assays and fluorescence-activated cell sorting analysis, we found that amitriptyline caused a marked reduction in HTB114 cell viability, associated with the parallel upregulation of p75(NTR) expression. This converted the TrKA⁺-proliferating cells into TrKA⁺/p75(NTR⁺), leading to downregulation of TrKA-prosurvival signaling (AKT) and activation of p75(NTR)-dependent apoptosis (through caspase-3). Overall, we provide novel evidence that HTB114 uterine leiomyosarcoma cells are highly sensitive to amitriptyline, supporting the role of p75(NTR)-dependent apoptosis as a novel cytotoxic mechanism of this drug and of p75(NTR) as an inducible stress receptor and a novel target in clinical oncology.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1097/CAD.0b013e328364312f | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
ProNGF and Neurodegeneration in Alzheimer's Disease.
Front Neurosci
February 2019
Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada.
Profound and early basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Alzheimer's disease (AD). Loss of synapses between basal forebrain and hippocampal and cortical target tissue correlates highly with the degree of dementia and is thought to be a major contributor to memory loss. BFCNs depend for their survival, connectivity and function on the neurotrophin nerve growth factor (NGF) which is retrogradely transported from its sites of synthesis in the cortex and hippocampus.
View Article and Find Full Text PDFproNGF inhibits proliferation and oligodendrogenesis of postnatal hippocampal neural stem/progenitor cells through p75NTR in vitro.
Stem Cell Res
September 2013
Neurobiology Laboratory, Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
Neural stem/progenitor cells (NSCs) proliferate and differentiate under tight regulation by various factors in the stem cell niche. Recent studies have shown that the precursor of nerve growth factor (NGF), proNGF, abounds in the central nervous system (CNS) and that its expression level in the brain is substantially elevated with aging as well as in several types of CNS disorders. In this study, we found for the first time that proNGF inhibited the proliferation of NSCs isolated from postnatal mouse hippocampus and caused cell cycle arrest in the G0/G1 phase without affecting apoptosis.
View Article and Find Full Text PDF3,3'-diindolylmethane induction of p75NTR-dependent cell death via the p38 mitogen-activated protein kinase pathway in prostate cancer cells.
Cancer Prev Res (Phila)
June 2009
Department of Biochemistry, the Vincent T Lombardi Comprehensive Cancer Center, Georgetown University Medical, University of the District of Columbia, Washington, DC 20057-1436, USA.
The p75(NTR) functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we showed that treatment with the nonsteroidal anti-inflammatory drug, indomethacin, induced p75(NTR) expression in the T24 cancer cell line leading to p75(NTR)-mediated decreased survival. Utilizing the indole moiety of indomethacin as a pharmacophore, we identified in rank-order with least efficacy, ketorolac, etodolac, indomethacin, 5-methylindole-3-acetic acid, indole-3-carbinol, and 3,3'-diindolylmethane (DIM) exhibiting greatest activity for induction of p75(NTR) levels and inhibition of cell survival.
View Article and Find Full Text PDFp75NTR-dependent modulation of cellular handling of reactive oxygen species.
J Neurochem
July 2009
Department of Pediatrics, University of Rochester, Rochester, New York 14642, USA.
Our previous studies demonstrated that p75NTR confers protection against oxidative stress-induced apoptosis upon PC12 cells; however, the mechanisms responsible for this effect are not known. The present studies reveal decreased mitochondrion membrane potential and increased generation of reactive oxygen species (ROS) in p75NTR-deficient PC12 cells as well as diminution of ROS generation after transfection of a full-length p75NTR construct into these cells. They also show that p75NTR deficiency attenuates activation of the phosphatidylinositol 3-kinase --> phospho-Akt/protein kinase B pathway in PC12 cells by oxidative stress or neurotrophic ligands and inhibition of Akt phosphorylation decreases the glutathione (GSH) content in PC12 cells.
View Article and Find Full Text PDFNeurotrophin-3 improves retinoic acid-induced neural differentiation of skin-derived precursors through a p75NTR-dependent signaling pathway.
Neurosci Res
June 2009
Division of Neuroscience, Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Skin-derived precursors (SKPs) are derived from mesoblast and can differentiate into smooth muscle cells, adipocytes, and less neuronal phenotypes. This study demonstrates that retinoic acid (RA) improves SKPs exit from self-proliferation to neural differentiation through up-regulating of NeuroD and cell-cycle regulatory protein p21, meanwhile RA also induces p75 neurotrophin receptor (p75NTR) up-regulation and apoptosis of SKPs. When treated sequentially with neurotrophin-3 (NT-3) after RA induction, the survival and neural differentiation of SKPs were enhanced significantly, and cell apoptosis induced by RA was decreased.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!