Stress hormones mediate drug resistance to paclitaxel in human breast cancer cells through a CDK-1-dependent pathway
Stress hormones mediate drug resistance to paclitaxel in human breast cancer cells through a CDK-1-dependent pathway
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DOI：
10.1016/j.psyneuen.2009.05.008
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发表时间：
2009-11-01
影响因子：
3.7
通讯作者：
Conrads, Thomas P.
中科院分区：
文献类型：
--
作者：
Flint, Melanie S.;Kim, Grace;Conrads, Thomas P.
化疗是乳腺癌成功治疗方案的一部分，然而，多达50%的患者会产生耐药性。癌症患者的压力可以等同于化疗反应差。我们推测耐药性可能与应激激素诱导的乳腺癌细胞改变有关。为了验证这一假设，用紫杉醇和/或皮质醇、去甲肾上腺素和肾上腺素培养MDA-MB-231细胞，并进行细胞毒性、细胞周期分析、基因组和蛋白质组分析。应激激素可显著逆转紫杉醇介导的细胞毒作用和G2/M期细胞周期停滞。基因组和蛋白质组学分析表明，应激激素调节β-微管蛋白亚型，并显著改变参与调控G2/M转变的基因和蛋白质，包括细胞周期蛋白依赖性激酶-1(CDK-1)。抑制CDK-1可阻断应激激素逆转紫杉醇诱导的细胞毒作用，提示应激激素的保护作用是通过依赖CDK-1的机制实现的。这些数据表明，应激激素干扰了紫杉醇的疗效，并显著地导致了耐药性。(C)2009爱思唯尔有限公司。保留所有权利。
Chemotherapy comprises part of successful treatment regimens for breast cancer, however, up to 50% of patients develop resistance. Stress in cancer patients can equate to poor chemotherapeutic responses. We hypothesize that drug resistance may be associated with stress hormone-induced alterations in breast cancer cells. To test this hypothesis, MDA-MB-231 cells were cultured with paclitaxel and/or cortisol, norepinephrine and epinephrine and cytotoxicity, cell cycle analyses, genomic and proteomic analyses were performed. Paclitaxel-mediated cytotoxicity and G2/M cell cycle arrest were reversed significantly by stress hormones. Genomic and proteomic analyses revealed that stress hormones modulated beta-tubulin isotypes and significantly altered genes and proteins involved in regulation of the G2/M transition, including cyclin-dependent kinase-1 (CDK-1). Inhibition of CDK-1 abrogated stress hormone-mediated reversal of paclitaxel-induced cytotoxicity, indicating that the protective effect of stress hormones act through a CDK-1-dependent mechanism. These data demonstrate that stress hormones interfere with paclitaxel efficacy and contribute significantly to drug resistance. (C) 2009 Elsevier Ltd. All rights reserved.