PloS one, 2013-10, Vol.8 (10), p.e76822
2013
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- Autor(en) / Beteiligte
- Titel
- Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways
- Ist Teil von
- PloS one, 2013-10, Vol.8 (10), p.e76822
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0076822Titel-ID: cdi_plos_journals_1440074905
- Format
- –
- Schlagworte
- Acetylation, AKT protein, Aminophenols - pharmacology, Animals, Autocrine signalling, Biomedical engineering, Blotting, Western, Cancer, Cell cycle, Cell Line, Cell Line, Tumor, Cell Membrane - metabolism, Cell Nucleus - metabolism, Cell proliferation, Cells, Cultured, Chromatin, Engineering, Epigenetics, Gastroenterology, Gastrointestinal cancer, Gastrointestinal Stromal Tumors - genetics, Gastrointestinal Stromal Tumors - metabolism, Gastrointestinal Stromal Tumors - pathology, Gene expression, Glycogen, Glycogen synthase kinase 3, Glycogen Synthase Kinase 3 - antagonists & inhibitors, Glycogen Synthase Kinase 3 - metabolism, Glycogen synthesis, Hepatic Stellate Cells - cytology, Hepatic Stellate Cells - metabolism, Hepatology, Histone H3, Histones - metabolism, Humans, Impact prediction, Inhibition, Insulin, Insulin-like growth factor I, Insulin-Like Growth Factor I - pharmacology, Insulin-like growth factors, Interstitial cells, Interstitial cells of Cajal, Interstitial Cells of Cajal - cytology, Interstitial Cells of Cajal - metabolism, Kinases, Ligands, Lysine, Maleimides - pharmacology, Methylation, Methylation - drug effects, Methyltransferase, Mice, Mice, Inbred BALB C, Mice, Knockout, Muscles, Mutation, Neurosciences, Nuclei, Nuclei (cytology), Paracrine signalling, Pathology, Peptides, Pharmacology, Physiology, Precision medicine, Proteins, Proto-Oncogene Proteins c-kit - genetics, Proto-Oncogene Proteins c-kit - metabolism, Receptor, IGF Type 1 - genetics, Receptor, IGF Type 1 - metabolism, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleic acid, RNA, RNA-mediated interference, Rodents, Sarcoma, Signal transduction, Signal Transduction - drug effects, Smooth muscle, Stem Cell Factor - genetics, Stem Cell Factor - metabolism, Stem cells, Transcription, Genetic - drug effects, Tumors