Molecular and cellular endocrinology, 2014-03, Vol.383 (1-2), p.69-79
2014
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Details
- Autor(en) / Beteiligte
- Titel
- Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer
- Ist Teil von
- Molecular and cellular endocrinology, 2014-03, Vol.383 (1-2), p.69-79
- Ort / Verlag
- Ireland: Elsevier Ireland Ltd
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Neuroendocrine (NE) differentiation has been attributed to the progression of castration-resistant prostate cancer (CRPC). Growth factor pathways including the epidermal growth factor receptor (EGFR) signaling have been implicated in the development of NE features and progression to a castration-resistant phenotype. However, upstream molecules that regulate the growth factor pathway remain largely unknown. Using androgen-insensitive bone metastasis PC-3 cells and androgen-sensitive lymph node metastasis LNCaP cells derived from human prostate cancer (PCa) patients, we demonstrated that γ-aminobutyric acid A receptor (GABAAR) ligand (GABA) and agonist (isoguvacine) stimulate cell proliferation, enhance EGF family members expression, and activate EGFR and a downstream signaling molecule, Src, in both PC-3 and LNCaP cells. Inclusion of a GABAAR antagonist, picrotoxin, or an EGFR tyrosine kinase inhibitor, Gefitinib (ZD1839 or Iressa), blocked isoguvacine and GABA-stimulated cell growth, trans-phospohorylation of EGFR, and tyrosyl phosphorylation of Src in both PCa cell lines. Spatial distributions of GABAAR α1 and phosphorylated Src (Tyr416) were studied in human prostate tissues by immunohistochemistry. In contrast to extremely low or absence of GABAAR α1-positive immunoreactivity in normal prostate epithelium, elevated GABAAR α1 immunoreactivity was detected in prostate carcinomatous glands. Similarly, immunoreactivity of phospho-Src (Tyr416) was specifically localized and limited to the nucleoli of all invasive prostate carcinoma cells, but negative in normal tissues. Strong GABAAR α1 immunoreactivity was spatially adjacent to the neoplastic glands where strong phospho-Src (Tyr416)-positive immunoreactivity was demonstrated, but not in adjacent to normal glands. These results suggest that the GABA signaling is linked to the EGFR pathway and may work through autocrine or paracine mechanism to promote CRPC progression.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0303-7207eISSN: 1872-8057DOI: 10.1016/j.mce.2013.11.017Titel-ID: cdi_proquest_miscellaneous_1678007886
- Format
- –
- Schlagworte
- Autocrine Communication - genetics, Cancer, Cell Line, Tumor, Cell Proliferation - drug effects, Epidermal growth factor, GABA Agonists - pharmacology, GABA Antagonists - pharmacology, gamma-Aminobutyric Acid - metabolism, gamma-Aminobutyric Acid - pharmacology, Gene Expression Regulation, Neoplastic, Growth factors, Human, Humans, Inhibitors, Isonicotinic Acids - pharmacology, Male, Paracrine Communication - genetics, Pathways, Phosphorylation - drug effects, Picrotoxin - pharmacology, Progressions, Prostate, Prostate - drug effects, Prostate - metabolism, Prostate - pathology, Prostate cancer, Prostatic Neoplasms - genetics, Prostatic Neoplasms - metabolism, Prostatic Neoplasms - pathology, Protein Kinase Inhibitors - pharmacology, Quinazolines - pharmacology, Receptor, Epidermal Growth Factor - genetics, Receptor, Epidermal Growth Factor - metabolism, Receptors, Receptors, GABA-A - genetics, Receptors, GABA-A - metabolism, Signal Transduction, Src, src-Family Kinases - genetics, src-Family Kinases - metabolism, γ-Aminobutyric acid receptor