A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway
A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway
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DOI：
10.1038/sj.onc.1210172
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发表时间：
2007-05-31
期刊：
影响因子：
8
通讯作者：
Sebti, S. M.
中科院分区：
文献类型：
--
作者：
Carie, A. E.;Sebti, S. M.
化学生物学方法鉴定了β 2肾上腺素能受体（β 2AR）激动剂ARA-211（吡特罗），在动物模型中引起细胞凋亡和人类肿瘤消退。b2AR刺激cAMP形成和蛋白激酶A （PKA）激活导致Raf-1（但不包括B-Raf）激酶失活，Mek-1激酶抑制和磷酸化细胞外信号调节激酶（Erk）1/2水平降低。ARA-211对Raf/Mek/Erk1/2通路的抑制是由PKA介导的，而不是由cAMP激活的交换蛋白（EPAC）。ARA-211具有选择性，可抑制P-Erk1/2，但不抑制P-JNK、P-p38、P-Akt或P-STAT3水平。b2AR刺激可抑制体外锚定依赖性和非依赖性生长，诱导细胞凋亡和体内肿瘤消退。b2AR拮抗剂和组成型活性Mek-1从ARA-211的作用中拯救出来，表明ARA-211的抗肿瘤活性需要b2AR刺激和Mek激酶抑制。此外，只有在人类肿瘤中，ARA-211诱导cAMP形成并降低P-Erk1/2水平，才会抑制生长。因此，b2AR刺激可以显著抑制癌症的恶性转化，通过camp依赖性的PKA激活而不是EPAC激活来阻断Raf-1/Mek-1/Erk1/2通路。
A chemical biology approach identifies a beta 2 adrenergic receptor (beta 2AR) agonist ARA-211 (Pirbuterol), which causes apoptosis and human tumor regression in animal models. b2AR stimulation of cAMP formation and protein kinase A (PKA) activation leads to Raf-1 (but not B-Raf) kinase inactivation, inhibition of Mek-1 kinase and decreased phospho-extracellular signal-regulated kinase (Erk)1/2 levels. ARA-211 inhibition of the Raf/Mek/Erk1/2 pathway is mediated by PKA and not exchange protein activated by cAMP (EPAC). ARA-211 is selective and suppresses P-Erk1/2 but not P-JNK, P-p38, P-Akt or P-STAT3 levels. b2AR stimulation results in inhibition of anchorage-dependent and -independent growth, induction of apoptosis in vitro and tumor regression in vivo. b2AR antagonists and constitutively active Mek-1 rescue from the effects of ARA-211, demonstrating that b2AR stimulation and Mek kinase inhibition are required for ARA-211 antitumor activity. Furthermore, suppression of growth occurs only in human tumors where ARA-211 induces cAMP formation and decreases P-Erk1/2 levels. Thus, b2AR stimulation results in significant suppression of malignant transformation in cancers where it blocks the Raf-1/Mek-1/Erk1/2 pathway by a cAMP-dependent activation of PKA but not EPAC.