beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways.
beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways.
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DOI：
10.4149/neo_2009_02_108
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发表时间：
2009
期刊：
影响因子：
3
通讯作者：
M. Zhao;G. Zhou;Y. Zhang;T. Chen;X. Sun;C. Stuart;G. Hanley;J. Li;J. Zhang;Deling Yin
中科院分区：
文献类型：
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作者：
M. Zhao;G. Zhou;Y. Zhang;T. Chen;X. Sun;C. Stuart;G. Hanley;J. Li;J. Zhang;Deling Yin
未标记的β-抑制蛋白是一个调节和支架蛋白家族，是包括阿片受体在内的G蛋白偶联受体（GPCR）的众所周知的负调节因子。最近的研究表明，β-arrestin 2在抑制细胞死亡方面发挥着潜在的作用。据报道，阿片样物质如吗啡在高浓度（>500 μ M持续24小时）下诱导细胞死亡，这与接受慢性吗啡治疗以缓解疼痛的癌症患者中的吗啡血浆浓度相似。然而，β-arrestin 2在阿片类药物诱导的细胞死亡中的作用仍有待阐明。我们在这里报告，β-arrestin 2显着阻断吗啡诱导的人乳腺癌MCF-7和MDA-MB 231细胞的细胞死亡数量。与单独抑制β-arrestin 2或吗啡治疗相比，通过特异性RNA干扰（RNAi）和吗啡治疗抑制内源性β-arrestin 2显著减弱磷酸化Akt的水平。然而，β-arrestin 2对吗啡诱导的细胞死亡的阻断似乎依赖于caspase-8的抑制，因为抑制β-arrestin 2和吗啡处理显著增强了切割的caspase-8的水平。这些研究首次表明β-arrestin 2通过抗凋亡Akt和促凋亡caspase-8途径阻断吗啡诱导的细胞死亡。因此，靶向β-arrestin 2可能有助于治疗阿片类药物作为癌症患者止痛药的副作用。关键词乳腺癌，β-arrestin，阿片类药物。Akt，caspase-8，细胞死亡。
UNLABELLED beta-arrestins, a family of regulatory and scaffold proteins, are well-known negative regulators of G-protein-coupled receptors (GPCRs) including opioid receptors. Recent studies have shown that beta-arrestin2 plays a potential role in inhibiting cell death. It has been reported that opioids such as morphine induce cell death at high concentrations (>500 microM for 24 hours), which is similar to morphine plasma concentrations in cancer patients receiving chronic morphine treatment for pain relievers. However, the role of beta-arrestin2 in opioid-induced cell death remains to be elucidated. We report here that beta-arrestin2 significantly blocks morphine-induced number of cell death in human breast cancer MCF-7 and MDA-MB231 cells. Suppression of endogenous beta-arrestin2 by specific RNA interfering (RNAi) and morphine treatment significantly attenuates the levels of phosphorylated Akt compared with inhibition of beta-arrestin2 or morphine treatment alone. However, blockade of morphine-induced cell death by beta-arrestin2 seems to be dependent on the inhibition of caspase-8, as inhibition of beta-arrestin2 and morphine treatment significantly enhanced the levels of cleaved caspase-8. These studies show for the first time that beta-arrestin2 blocks morphine-induced cell death through anti-apoptotic Akt and pro-apoptotic caspase-8 pathways. Therefore, targeting beta-arrestin2 may be useful for treating side effects of opioids as pain relievers for cancer patients. KEYWORDS Breast cancer, beta-arrestin, opioid. Akt, caspase-8,cell death.