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Background: High-grade chondrosarcoma, which has a high incidence of local recurrence and pulmonary metastasis despite surgical resection, is associated with poor prognosis. Therefore, new and effective adjuvant therapies are urgently required for this disease. Gamma-aminobutyric acid (GABA), which acts as a neurotrophic factor during nervous system development, is related to the proliferation and migration of certain cancer cells. The GABAergic system, which is composed of GABA, the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), and GABA receptors, has an important function in nerve growth and development of neural crest. Therefore, the GABAergic system may play important functional roles in the proliferation of chondrosarcoma cells, which are derived from neural crest cells. We examined the anti-tumor effects of the GABAergic system on a chondrosarcoma cell line.

Methods: We evaluated the underlying mechanisms of the anti-tumor effects of the GABAergic system, such as the involvement of different signaling pathways, apoptosis, and cell cycle arrest, in the high-grade chondrosarcoma cell line OUMS-27. In addition, we performed whole-cell patch-clamp recordings for Ca 2+ currents and evaluated the changes in intracellular Ca 2+ concentration via Ca 2+ channels, which are related to the GABA B receptor in high-grade chondrosarcoma cells.

Results: The GABA B receptor antagonist CGP had anti-tumor effects on high-grade chondrosarcoma cells in a dose-dependent manner. The activities of caspase 3 and caspase 9 were significantly elevated in CGP-treated cells compared to in untreated cells. The activity of caspase 8 did not differ significantly between untreated cells and CGP-treated cells. However, caspase 8 tended to be up-regulated in CGP-treated cells. The GABA B receptor antagonist exhibited anti-tumor effects at the G1/S cell cycle checkpoint and induced apoptosis via dual inhibition of the PI3/Akt/mTOR and MAPK signaling pathways. Furthermore, the changes in intracellular Ca 2+ via GABA B receptor-related Ca 2+ channels inhibited the proliferation of high-grade chondrosarcoma cells by inducing and modulating apoptotic pathways.

Conclusions: The GABA B receptor antagonist may improve the prognosis of high-grade chondrosarcoma by exerting anti-tumor effects via different signaling pathways, apoptosis, cell cycle arrest, and Ca 2+ channels in high-grade chondrosarcoma cells.

Titel:	GABA <subscript>B</subscript> receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways.
Autor/in / Beteiligte Person:	Kanbara, K ; Otsuki, Y ; Watanabe, M ; Yokoe, S ; Mori, Y ; Asahi, M ; Neo, M
Link:	Zum Volltext
Zeitschrift:	BMC cancer, Jg. 18 (2018-03-07), Heft 1, S. 263
Veröffentlichung:	London : BioMed Central, [2001-, 2018
Medientyp:	academicJournal
ISSN:	1471-2407 (electronic)
DOI:	10.1186/s12885-018-4149-4
Schlagwort:	Bone Neoplasms metabolism Cell Cycle Chondrosarcoma metabolism GABA-B Receptor Antagonists pharmacology Humans Patch-Clamp Techniques Receptors, GABA-B chemistry Signal Transduction Tumor Cells, Cultured Apoptosis Bone Neoplasms pathology Calcium metabolism Cell Proliferation Chondrosarcoma pathology Receptors, GABA-B metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [BMC Cancer] 2018 Mar 07; Vol. 18 (1), pp. 263. <i>Date of Electronic Publication: </i>2018 Mar 07. MeSH Terms: Apoptosis* ; Cell Proliferation* ; Bone Neoplasms / pathology ; Calcium / metabolism ; Chondrosarcoma / pathology ; Receptors, GABA-B / metabolism ; Bone Neoplasms / metabolism ; Cell Cycle ; Chondrosarcoma / metabolism ; GABA-B Receptor Antagonists / pharmacology ; Humans ; Patch-Clamp Techniques ; Receptors, GABA-B / chemistry ; Signal Transduction ; Tumor Cells, Cultured References: G Chir. 2010 Nov-Dec;31(11-12):568-74. (PMID: 21232206) ; Histol Histopathol. 2009 Aug;24(8):1009-19. (PMID: 19554508) ; Endocrinology. 2007 Oct;148(10):4984-92. (PMID: 17615148) ; J Cell Biochem. 2014 Sep;115(9):1624-35. (PMID: 24788582) ; Eur J Med Res. 2010 Oct 25;15(10):456-60. (PMID: 21156405) ; Eur J Neurosci. 1998 May;10(5):1654-66. 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(PMID: 10604925) Grant Information: Grant No. 20591768 International a Grant-in-Aid for Scientific Research from Japan Society for the promotion of Science, Japan Contributed Indexing: Keywords: Akt signaling; Apoptosis; Ca2+ channel; Cell cycle arrest; Chondrosarcoma; GABAB receptor; MAPK pathway; OUMS-27 cells; Whole cell patch clamp Substance Nomenclature: 0 (GABA-B Receptor Antagonists) ; 0 (Receptors, GABA-B) ; SY7Q814VUP (Calcium) Entry Date(s): Date Created: 20180309 Date Completed: 20180830 Latest Revision: 20240314 Update Code: 20240314 PubMed Central ID: PMC5842535

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GABA <subscript>B</subscript> receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways.