Xu Xin, Khater Mostafa, Wu Guangyu
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States.
Front Pharmacol. 2022 Oct 13;13:1009380. doi: 10.3389/fphar.2022.1009380. eCollection 2022.
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 β-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 μM and an efficiency comparable to other receptor agonists. We also find that CRISPR-Cas9-mediated knockout of Golgi-translocating Gγ9 subunit, phosphoinositide 3-kinase γ (PI3Kγ) and the small GTPase ADP-ribosylation factor 1 (ARF1), as well as pharmacological inhibition of Gβγ, PI3Kγ and Golgi-localized ARF1, each abolishes ERK1/2 activation by β-ionone. We further show that β-ionone significantly promotes ARF1 translocation to the Golgi and activates ARF1 that can be inhibited by Gγ9 and PI3Kγ depletion. Collectively, our data demonstrate that OR51E2 activates ERK1/2 through the Gβγ-PI3Kγ-ARF1 pathway that occurs spatially at the Golgi, and also provide important insights into MAPK hyper-activation in prostate cancer.
嗅觉受体OR51E2在前列腺组织中异位表达并调节前列腺癌进展，但其在致癌性丝裂原活化蛋白激酶（MAPK）激活中的功能和调控机制尚不明确。在此，我们证明β-紫罗兰酮，一种OR51E2激动剂，在前列腺癌细胞中呈剂量依赖性激活细胞外信号调节激酶1和2（ERK1/2），其半数有效浓度（EC50）约为20μM，激活效率与其他受体激动剂相当。我们还发现，CRISPR-Cas9介导的高尔基体转运Gγ9亚基、磷酸肌醇3激酶γ（PI3Kγ）和小GTP酶ADP核糖基化因子1（ARF1）的敲除，以及对Gβγ、PI3Kγ和高尔基体定位的ARF1的药理学抑制，均消除了β-紫罗兰酮对ERK1/2的激活作用。我们进一步表明，β-紫罗兰酮显著促进ARF1向高尔基体的转运并激活ARF1，而Gγ9和PI3Kγ的缺失可抑制这种激活。总体而言，我们的数据表明OR51E2通过在高尔基体空间发生的Gβγ-PI3Kγ-ARF1途径激活ERK1/2，这也为前列腺癌中MAPK的过度激活提供了重要见解。
