蛋白靶点的低氧微环境抑制抗癌药物疗效
生物通 · 2013/06/28
科研人员在一项突破性进展中发现,低氧条件影响了mTOR蛋白抑制药物对肿瘤的治疗效果,而在实体瘤中普遍存在的低氧环境阐明了这一疗法达不到疗效的原因,该研究为克服这一治疗困境提供了新线索。

耶路撒冷希伯莱大学的研究人员在癌症研究中取得了一项突破性进展,他们分析了低氧条件对一种热门抗癌疗法的影响,阐明了这一疗法不能达到预期疗效的原因,为打破这一僵局提供了新的线索。文章发表在本期的美国国家科学院院刊PNAS杂志上。

蛋白mTOR是雷帕霉素在哺乳动物中的作用目标,能够调节细胞对环境信号的应答。人们发现,mTOR在许多实体瘤中被强力激活,因此将其作为癌症治疗中的重要靶标。不过此前的研究显示,虽然通过药物抑制mTOR能够成功杀死肿瘤外层的癌细胞,但这类药物在临床试验中,对肿瘤中心的细胞效果并不理想。

低氧是几乎所有实体瘤都具备的普遍特性,能够促进癌细胞的糖酵解、细胞增殖和血管生成。低氧条件能够影响肿瘤对药物治疗的应答。此前科学家们已经知道,mTOR信号传导会受到低氧条件的影响和改变,但并不清楚这一过程中的具体机制。

耶路撒冷希伯莱大学的Raphael D. Levine教授及其同事,在脑癌模型中对低氧条件进行了分析,希望明确低氧条件影响mTOR信号的机制,找到mTOR药物疗效不佳的原因。

为此,他们采用新型微芯片技术,来检测单个癌细胞中的mTOR信号网络,并在物理学理论的基础上对数据进行解读,使复杂的生物学系统简单化。

研究人员对实体瘤中的常见低氧水平进行了研究,发现在这一条件下,mTOR相关的信号网络会发生转变,使这一通路无法正常应答mTOR药物的治疗。研究人员将上述转变解读为一种相变,并通过实验进行了验证。

研究显示,在1.5% pO2(oxygen partial pressure)下,mTOR信号通路无法应答mTOR激酶抑制剂。而在1.5% pO2以上,抑制剂能够发挥正常作用。研究人员指出,这种相变是信号网络中的转换点,发生得非常突然。一旦信号传导发生转变,细胞就不会再以之前的方式进行响应。也就是说,此时mTOR药物对肿瘤无法继续起到抑制作用。

这项研究明确了mTOR抑制剂临床效果不佳的原因,为人们展现了生物学过程的复杂性,而这种复杂性正是人们在寻找疾病治疗方法时遇到的主要障碍之一。

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
查看更多
  • Hypoxia induces a phase transition within a kinase signaling network in cancer cells

    Hypoxia is a near-universal feature of cancer, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. In a glioblastoma multiforme (GBM) cancer cell model, we examined the response of signaling networks to targeted pathway inhibition between 21% and 1% pO2. We used a microchip technology that facilitates quantification of a panel of functional proteins from statistical numbers of single cells. We find that near 1.5% pO2, the signaling network associated with mammalian target of rapamycin (mTOR) complex 1 (mTORC1)—a critical component of hypoxic signaling and a compelling cancer drug target—is deregulated in a manner such that it will be unresponsive to mTOR kinase inhibitors near 1.5% pO2, but will respond at higher or lower pO2 values. These predictions were validated through experiments on bulk GBM cell line cultures and on neurosphere cultures of a human-origin GBM xenograft tumor. We attempt to understand this behavior through the use of a quantitative version of Le Chatelier’s principle, as well as through a steady-state kinetic model of protein interactions, both of which indicate that hypoxia can influence mTORC1 signaling as a switch. The Le Chatelier approach also indicates that this switch may be thought of as a type of phase transition. Our analysis indicates that certain biologically complex cell behaviors may be understood using fundamental, thermodynamics-motivated principles.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test