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

Wu, Weijuan; Yang, Qing; Fung, Kar Ming; Humphreys, Mitchell R.; Brame, Lacy; Cao, Amy; Fang, Yu Ting; Shih, Pin Tsen; Kropp, Bradley P.; Lin, Hsueh Kung

doi:10.1016/j.mce.2013.11.017

Cited by 25 publications

(28 citation statements)

References 39 publications

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“…How the AKT pathway is regulated by Gabra3 remains to be further studied. Although it has been shown that GABA A receptor regulates EGFR activation in prostate cancer 42 , our results indicate that this is not the case in breast cancer cells ( Supplementary Fig. 8 ).…”

Section: Discussioncontrasting

confidence: 81%

The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis

et al. 2016

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Metastasis is a critical event affecting breast cancer patient survival. To identify molecules contributing to the metastatic process, we analysed The Cancer Genome Atlas (TCGA) breast cancer data and identified 41 genes whose expression is inversely correlated with survival. Here we show that GABAA receptor alpha3 (Gabra3), normally exclusively expressed in adult brain, is also expressed in breast cancer, with high expression of Gabra3 being inversely correlated with breast cancer survival. We demonstrate that Gabra3 activates the AKT pathway to promote breast cancer cell migration, invasion and metastasis. Importantly, we find an A-to-I RNA-edited form of Gabra3 only in non-invasive breast cancers and show that edited Gabra3 suppresses breast cancer cell invasion and metastasis. A-to-I-edited Gabra3 has reduced cell surface expression and suppresses the activation of AKT required for cell migration and invasion. Our study demonstrates a significant role for mRNA-edited Gabra3 in breast cancer metastasis.

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Section: Discussioncontrasting

confidence: 81%

The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis

et al. 2016

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“…It has been reported that GABA simulated proliferation of PC-3 cells (Wu et al, 2014). In this study, baclofen displayed no effect on the survival of PC-3 cells, but GABA B R antagonist CGP54626 inhibited cell survival.…”

Section: Discussionmentioning

confidence: 40%

GABA_BR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells

Xia

Zhu

et al. 2017

Mol Pharmacol

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G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABA receptor (GABAR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABAR has been detected in human cancer tissues and cancer cell lines, but the role of GABAR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABAR hijacks RTK signaling to modulate the fates of human prostate cancer cells. RTK array analysis revealed that the GABAR-specific agonist baclofen selectively induced the transactivation of EGFR in PC-3 cells. EGFR transactivation resulted in the activation of ERK1/2 by a mechanism that is dependent on G protein and that requires matrix metalloproteinase-mediated proligand shedding. Positive allosteric modulators (PAMs) of GABAR, such as CGP7930, rac-BHFF, and GS39783, can function as PAM agonists to induce EGFR transactivation and subsequent ERK1/2 activation. Moreover, both baclofen and CGP7930 promoted cell migration and invasion through EGFR signaling. In summary, our observations demonstrated that GABAR transactivated EGFR in a ligand-dependent mechanism to promote prostate cancer cell migration and invasion, thus providing new insights into developing a novel strategy for prostate cancer treatment by targeting neurotransmitter signaling.

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“…The effects of GABA A receptor agonists [ 20 , 30 ] and antagonists [ 31 ] reportedly vary in different types of cancer cells. Similarly, several reports indicated that GABA B receptor agonists and GABA inhibited cell proliferation and migration in gastric cancer [ 32 ], colon cancer [ 33 ], and malignant hepatocytes [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

GABAB receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways

et al. 2018

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BackgroundHigh-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.MethodsWe 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 Ca2+ currents and evaluated the changes in intracellular Ca2+ concentration via Ca2+ channels, which are related to the GABAB receptor in high-grade chondrosarcoma cells.ResultsThe GABAB 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 GABAB 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 Ca2+ via GABAB receptor-related Ca2+ channels inhibited the proliferation of high-grade chondrosarcoma cells by inducing and modulating apoptotic pathways.ConclusionsThe GABAB receptor antagonist may improve the prognosis of high-grade chondrosarcoma by exerting anti-tumor effects via different signaling pathways, apoptosis, cell cycle arrest, and Ca2+ channels in high-grade chondrosarcoma cells.

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

Cited by 25 publications

References 39 publications

The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis

The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis

GABA_BR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells

GABAB receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways

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

Cited by 25 publications

References 39 publications

The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis

The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis

GABABR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells

GABAB receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways

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GABA_BR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells