期刊
FRONTIERS IN PHARMACOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.1009380
关键词
G protein-coupled receptor; G beta gamma; PI3K gamma; ARF1; Golgi translocation; ERK1; 2; prostate cancer
资金
- NIH
- [R35GM136397]
The olfactory receptor OR51E2 is ectopically expressed in prostate tissues and regulates prostate cancer progression. A study demonstrated that beta-ionone, an OR51E2 agonist, activates ERK1/2 pathway in prostate cancer cells. The activation of ERK1/2 by beta-ionone is regulated by Golgi-translocating G gamma 9 subunit, PI3K gamma, and ARF1.
The olfactory receptor OR51E2 is ectopically expressed in prostate tissues and regulates prostate cancer progression, but its function and regulation in oncogenic mitogen-activate protein kinase (MAPK) activation are poorly defined. Here we demonstrate that beta-ionone, an OR51E2 agonist, dose-dependently activates extracellular signal-regulated kinases 1 and 2 (ERK1/2) in prostate cancer cells, with an EC50 value of approximate 20 mu M and an efficiency comparable to other receptor agonists. We also find that CRISPR-Cas9-mediated knockout of Golgi-translocating G gamma 9 subunit, phosphoinositide 3-kinase gamma (PI3K gamma) and the small GTPase ADP-ribosylation factor 1 (ARF1), as well as pharmacological inhibition of G beta gamma, PI3K gamma and Golgi-localized ARF1, each abolishes ERK1/2 activation by beta-ionone. We further show that beta-ionone significantly promotes ARF1 translocation to the Golgi and activates ARF1 that can be inhibited by G gamma 9 and PI3K gamma depletion. Collectively, our data demonstrate that OR51E2 activates ERK1/2 through the G beta gamma-PI3K gamma-ARF1 pathway that occurs spatially at the Golgi, and also provide important insights into MAPK hyper-activation in prostate cancer.
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