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

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

Research output: Contribution to journalArticle

7 Scopus citations

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 (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.

Original languageEnglish
Pages (from-to)69-79
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume383
Issue number1-2
DOIs
StatePublished - 1 Dec 2013

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Keywords

  • γ-Aminobutyric acid receptor
  • Epidermal growth factor
  • Prostate cancer
  • Src

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