title: 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.affiliation: Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
authors.forename: Kar-Ming
authors.initials: KM
authors.lastname: Fung
authors.affiliation: Department of Urology, Mayo Clinic, Phoenix, AZ 85054, USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Humphreys
authors.affiliation: Department of Psychology, University of Oklahoma, Norman, OK 73019, USA.
authors.forename: Lacy S
authors.initials: LS
authors.lastname: Brame
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Cao
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91207, Taiwan, ROC.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Fang
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91207, Taiwan, ROC.
authors.forename: Pin-Tsen
authors.initials: PT
authors.lastname: Shih
authors.affiliation: Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Kropp
authors.affiliation: Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: hk-lin@ouhsc.edu.
authors.forename: Hsueh-Kung
authors.initials: HK
authors.lastname: Lin
mesh_terms: D019898:Autocrine Communication / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007539:Isonicotinic Acids / Q000494:pharmacology; D008297:Male; D019899:Paracrine Communication / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D010852:Picrotoxin / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D018755:GABA Agonists; D018756:GABA Antagonists; D000077156:Gefitinib; D007539:Isonicotinic Acids; D010852:Picrotoxin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D019061:src-Family Kinases; C512478:EGFR protein, human; C015300:isoguvacine
keywords: Epidermal growth factor; Prostate cancer; Src; γ-Aminobutyric acid receptor