GABABR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells
GABABR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells
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GABA(B)R 诱导的 EGFR 反式激活促进人前列腺癌细胞的迁移
DOI：
10.1124/mol.116.107854
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发表时间：
2017-09-01
影响因子：
3.6
通讯作者：
Liu, Jianfeng
中科院分区：
文献类型：
--
作者：
Xia, Shuai;He, Cong;Liu, Jianfeng
G蛋白偶联受体（gpcr）和受体酪氨酸激酶（rtk）协同作用，调节细胞生长、增殖、存活和迁移。代谢性GABA(B)受体（GABA(B)R）是中枢神经系统中主要抑制性神经递质GABA的GPCR。GABA(B)R在人类癌症组织和癌细胞系中表达增加，但GABA(B)R在这些细胞中的作用存在争议，其潜在机制尚不清楚。在这里，我们研究了GABA(B)R是否劫持RTK信号来调节人类前列腺癌细胞的命运。RTK阵列分析显示，GABA(B) r特异性激动剂巴氯芬选择性诱导PC-3细胞中EGFR的反激活。EGFR反激活通过一种依赖于G（i/o）蛋白的机制导致ERK1/2的激活，这需要基质金属蛋白酶介导的前配体脱落。GABA(B)R的阳性变构调节剂（PAM），如CGP7930、rac-BHFF和GS39783，可以作为PAM激动剂诱导EGFR转激活和随后的ERK1/2激活。此外，巴氯芬和CGP7930均通过EGFR信号传导促进细胞迁移和侵袭。综上所述，我们的观察结果表明，GABA(B)R以配体依赖的机制反激活EGFR，促进前列腺癌细胞的迁移和侵袭，从而为开发靶向神经递质信号治疗前列腺癌的新策略提供了新的见解。
G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABA(B) receptor (GABA(B)R) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABA(B)R has been detected in human cancer tissues and cancer cell lines, but the role of GABA(B)R in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABA(B)R hijacks RTK signaling to modulate the fates of human prostate cancer cells. RTK array analysis revealed that the GABA(B)R-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(i/o) protein and that requires matrix metalloproteinase-mediated proligand shedding. Positive allosteric modulators (PAMs) of GABA(B)R, 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 GABA(B)R 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.