Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer.
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.
['Wu|Weijuan|W|', 'Yang|Qing|Q|', 'Fung|Kar-Ming|KM|', 'Humphreys|Mitchell R|MR|', 'Brame|Lacy S|LS|', 'Cao|Amy|A|', 'Fang|Yu-Ting|YT|', 'Shih|Pin-Tsen|PT|', 'Kropp|Bradley P|BP|', 'Lin|Hsueh-Kung|HK|']
D019898:Autocrine Communication D045744:Cell Line, Tumor D049109:Cell Proliferation D066246:ErbB Receptors D018755:GABA Agonists D018756:GABA Antagonists D000077156:Gefitinib D015972:Gene Expression Regulation, Neoplastic D006801:Humans D007539:Isonicotinic Acids D008297:Male D019899:Paracrine Communication D010766:Phosphorylation D010852:Picrotoxin D011467:Prostate D011471:Prostatic Neoplasms D047428:Protein Kinase Inhibitors D011799:Quinazolines D011963:Receptors, GABA-A D015398:Signal Transduction D005680:gamma-Aminobutyric Acid D019061:src-Family Kinases
Epidermal growth factor Prostate cancer Src γ-Aminobutyric acid receptor