GABAB receptor is a novel drug target for pancreatic cancer
| العنوان: | GABAB receptor is a novel drug target for pancreatic cancer |
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| المؤلفون: | Hildegard M. Schuller, Mourad Majidi, Hussein A.N. Al-Wadei |
| المصدر: | Cancer. 112:767-778 |
| بيانات النشر: | Wiley, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | MAPK/ERK pathway, Baclofen, Cancer Research, medicine.medical_specialty, endocrine system diseases, GABA Agents, Blotting, Western, GABAB receptor, Biology, Article, gamma-Aminobutyric acid, Cell Line, Receptors, GABA, Cell Movement, Cell Line, Tumor, Pancreatic cancer, Internal medicine, Cyclic AMP, medicine, Humans, GABA Agonists, gamma-Aminobutyric Acid, Cell Proliferation, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Cell growth, Isoproterenol, Cell migration, Adrenergic beta-Agonists, medicine.disease, Immunohistochemistry, Enzyme Activation, Pancreatic Neoplasms, Endocrinology, Bromodeoxyuridine, Oncology, Cancer research, RNA Interference, Signal transduction, Signal Transduction, medicine.drug |
| الوصف: | Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death. Smoking, diabetes, and pancreatitis are risk factors. It has been shown that the growth of PDAC and pancreatic duct epithelial cells is regulated by beta-adrenoreceptors (beta-ARs). The activity of beta-ARs in the central nervous system is counteracted by gamma-aminobutyric acid (GABA) via GABA B receptor-mediated inhibition of adenylyl cyclase. The aim of the study was to investigate if GABA B R inhibits beta-AR signaling in PDAC and pancreatic duct epithelial cells, thus blocking driving forces of cancer progression, such as cell proliferation and cell migration.Intracellular cAMP was measured by immunoassays, DNA synthesis by BrdU incorporation assays, activation of ERK1/2 by ERK activation assays, and Western blots and metastatic potential by cell migration assays in the human PDAC cell lines PANC-1 and BXPC-3 and immortalized human pancreatic duct epithelial cells HPDE6-C7. The expression of norepinephrine, PKAR IIalpha, and GABA in PDAC microarrays was assessed by immunohistochemistry. RESULTS.: Stimulation of the GABA B R by GABA or baclofen inhibited isoproterenol-induced cAMP signaling below base levels. ERK1/2 activity in response to isoproterenol was blocked by GABA, an effect enhanced by transient overexpression of the GABA B R and abolished by GABA B R knockdown. DNA synthesis and cell migration were stimulated by isoproterenol, responses blocked by GABA and baclofen. Norepinephrine and PKAR IIalpha were overexpressed while GABA was underexpressed in human PDAC tissue arrays.The data suggest the stimulation of GABA B R signaling as a novel target for the treatment and prevention of pancreatic cancer. |
| تدمد: | 1097-0142 0008-543X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f9d9cc78b859e4927e413968e1f6bf29Test https://doi.org/10.1002/cncr.23231Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f9d9cc78b859e4927e413968e1f6bf29 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10970142 0008543X |
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