【专辑】细胞信号通路与癌症治疗
2016/02/25
2月16日的SCIENCESIGNALING为细胞信号通路与癌症治疗的专辑,发表了编者案“当细胞生物学遇到癌症治疗”,介绍本期和往期该杂志发表的关于细胞信号通路领域相关癌症治疗方面的内容,在这方面做了一个很好的概括。


2月16日的SCIENCESIGNALING为细胞信号通路与癌症治疗的专辑,发表了编者案“当细胞生物学遇到癌症治疗”,介绍本期和往期该杂志发表的关于细胞信号通路领域相关癌症治疗方面的内容,在这方面做了一个很好的概括。

生长和分化的细胞,包括癌细胞对代谢要求很高,因为它们必须建立新的蛋白质、膜和核酸。干扰细胞代谢和高分子生物合成的药物可以触发不同类型的细胞压力信号通路,比如那些涉及蛋白毒性的压力。而后未折叠的蛋白积累会引起内质网压力。细胞对应蛋白毒性压力会产生温度、氧化和内质网营养缺失等细胞整体压力。细胞整体压力抑制大不凡的蛋白质翻译,大部分都由压力活化转录因子ATF4调节。持续的蛋白毒性压力会导致细胞死亡。

1
药物ONC201

在本期SCIENCESIGNALING中Kline 和Ishizawa等人的研究显示ONC201,一个已经在临床实验的药物,在血液癌症和固体癌症来源的细胞中,都通过引起整体细胞压力引起细胞死亡。这两篇文章显示ONC201诱导ATF4的活化,这在固体肿瘤中增加了编码死亡受体基因和它的配体的表达,在淋巴瘤和白血病细胞中抑制生长促进激酶复合体mTORC1。ONC201引发的凋亡并不需要在很多肿瘤中突变的肿瘤抑制因子和转录因子p53的活性。

2
HER2阳性与内质网

细胞适应内质网压力的一个方法是增加一个称为内质网相关降解的过程。这个过程通过将它们转运出内质网并作为蛋白酶体的降解目标。Singh等发现生长受体HER2阳性的乳腺癌细胞会增加内质网压力的信号通路并增加内质网相关降解而生存下来。因为HER2的信号促进蛋白质合成,当细胞出现严重的蛋白毒性压力的时候,内质网相关降解受阻。用药物阻断在HER2阳性细胞的这一途径,会引起细胞的死亡。

3
PI3K-AKT通路

生长因子信号通路刺激磷酸肌醇3-激酶(PI3K)-AKT通路。在营养丰富的时候活化这个通路会激活mTOR激酶的活性,作为mTORC1复合物的一部分通过磷酸化转录因子4EBF1来促进蛋白转录。肿瘤细胞内在的或获得性抗性限制了抑制mTORC1活性或PI3K-AKT通路的药物的临床应用。Hsieh等人发现4EBP1的表达的内在差异和蛋白合成率,和细胞致瘤的倾向以及在小鼠中以mTOR为靶、人中以PI3K为靶的治疗抗性相关。上皮细胞癌变,往往有较高的4EBP1丰度和较低的蛋白质合成率。这些数据解释了为什么靶向这个信号通路的药物在治疗前列腺癌中是无效的,尽管在培养细胞中显示药物抗性和4EBP1丢失和较高的蛋白质合成率是相关的。这项研究突出了了解特定癌症细胞特异性并优化治疗方法的重要性。

4
SYNJ2基因

到达细胞膜的跨膜受体并不永久地呆在那里,而是经历了动态的内吞作用和循环回到细胞表面或者进入溶酶体降解。Ben-Chetrit的研究发现很多侵袭性乳腺癌肿瘤患者SYNJ2表达增加,该基因编码脂质磷酸酶synaptojanin 2。响应表皮生长因子EGF,SYNJ2位于和细胞侵袭性行为相关的片状伪足和侵袭伪足处,是EGF激活受体促进细胞迁移的区域。敲除SYNJ2基因抑制了EGF再循环到细胞表面,在培养的乳腺癌细胞中减少了侵袭行为。当移植到小鼠体内时,乳腺癌细胞表达一个磷酸酶缺乏的SYNJ2突变,产生较小的、较少转移性的肿瘤。让人鼓舞的是,在化合物筛选中已经鉴定了SYNJ2抑制剂在三维培养细胞系中降低了细胞的侵袭,中表明它可能以SYNJ2为靶标从而防止乳腺癌转移。

5
激酶BRAF

除了内吞和转运受体,内涵体也可以作为组织信号复合物的地方。激酶BRAF通常是由生长因子信号通路激活,这种激酶的突变导致结肠癌。Margalef等发现内涵体相关激酶TAK1将另外一个蛋白酶水解片段激酶IKKα磷酸化,BRAF突变的结肠细胞需要TAK1调节的IKKα的磷酸化为了转移和增殖裂解产物。内涵体是个酸性的场所,酸化抑制了IKKα的磷酸化、裂解产物和细胞死亡。这个研究反应了内涵体和核因子κB (NF-κB) 以及由BRAF激活的蛋白激酶途径意想不到的关系。

信号通路与新疗法

这些研究不仅强调了能够杀死癌细胞或阻止其增殖的化合物的重要性,也让大家了解它们如何工作,以确定癌症患者最有可能响应的一个特定治疗。此外这些文章是使用一个分子理解与细胞压力反应相关的信号通路事件的例子,会影响新的治疗方法或是发展更有效的组合治疗法。

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  • Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer

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