Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer.

Abstract

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 (GABA(A)R) 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 GABA(A)R 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 GABA(A)R α₁-positive immunoreactivity in normal prostate epithelium, elevated GABA(A)R 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.

• Authors: Weijuan Wu, Qing Yang, Kar-Ming Fung, Mitchell R Humphreys, Lacy S Brame, Amy Cao, Yu-Ting Fang, Pin-Tsen Shih, Bradley P Kropp, Hsueh-Kung Lin
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 383 Issue 1-2 Pg. 69-79 (Mar 05 2014) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 24296312 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• GABA Agonists
• GABA Antagonists
• Isonicotinic Acids
• Protein Kinase Inhibitors
• Quinazolines
• Receptors, GABA-A
• Picrotoxin
• gamma-Aminobutyric Acid
• EGFR protein, human
• ErbB Receptors
• src-Family Kinases
• Gefitinib
• isoguvacine

Topics

• Autocrine Communication (genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• ErbB Receptors (genetics, metabolism)
• GABA Agonists (pharmacology)
• GABA Antagonists (pharmacology)
• Gefitinib
• Gene Expression Regulation, Neoplastic
• Humans
• Isonicotinic Acids (pharmacology)
• Male
• Paracrine Communication (genetics)
• Phosphorylation (drug effects)
• Picrotoxin (pharmacology)
• Prostate (drug effects, metabolism, pathology)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• Receptors, GABA-A (genetics, metabolism)
• Signal Transduction
• gamma-Aminobutyric Acid (metabolism, pharmacology)
• src-Family Kinases (genetics, metabolism)