Nat Cell Biol:二甲双胍的抗癌机密?“饿死”癌细胞的关键在于天冬氨酸

2018-07-03 浮苏 生物探索

从活生物体中取出肿瘤细胞在培养皿中培养,它们会比以前繁殖得更快,产生这种结果的原因一直未知。现在,麻省理工学院的一组研究人员提出,活生物体的生长限制可能由细胞的生长环境导致。更具体地说,他们发现,在限制氧气的情况下,天冬氨酸是癌细胞增殖所需的关键营养素。

在这项研究中,科学家们通过从不同的组织类型中提取癌细胞,并利用编码豚鼠酶的基因将一种更丰富的底物转化为天冬氨酸。结果发现,培养皿中的癌细胞没有受到影响,但是,当这一批细胞被植入小鼠体内后,肿瘤生长速度比以前更快。进一步地,研究人员增加细胞的天冬氨酸供应,并成功加速了(癌细胞在)生物体内的增殖。

这项研究于6月25日发表在Nature Cell Biology杂志上,麻省理工学院范德海登实验室的Lucas Sullivan为该研究第一作者兼通讯作者。

天冬氨酸的制备

分离一个可能影响机体内肿瘤生长的单一因素是一件棘手的事情。2015年,研究生Dan Gui与Sullivan教授提出了一个颇具争议的问题:为什么细胞需要通过细胞呼吸消耗氧气才能增殖呢?

这是一个相当反直觉的问题,因为一些科学文献的结论已指出:生物体内的癌细胞不能像在培养皿中那样获得足够的氧气,因此不能依靠氧气产生足够的能量来分裂。相反,它们会转变成一个不需要氧气的发酵过程。但Sullivan和Dan Gui指出,癌细胞之所以依赖氧气,还有另一个原因:产生天冬氨酸作为副产品。

他们很快证实,天冬氨酸实际在控制癌细胞增殖速度方面发挥了关键作用。在一年后的另一项研究中,Sullivan和Dan Gui指出,已知抑制线粒体的抗糖尿病药物二甲双胍减缓了肿瘤生长并降低了体内细胞中天冬氨酸的水平。由于线粒体是细胞呼吸的关键,Sullivan推断,在已经缺氧的肿瘤环境中阻断线粒体的功能可能会使癌细胞更容易受到呼吸的进一步抑制,这可以解释为什么二甲双胍似乎对肿瘤生长有强烈的影响。

天冬氨酸是我们血液中浓度最低的氨基酸之一,除非存在一种罕见的蛋白质转运体,否则无法进入我们的细胞。因此,天冬氨酸很难从外界获得,即使在富氧环境下也是一样。

细胞获得天冬氨酸最简单的方法就是直接从内部生成,即分解另一种叫做天冬酰胺(asparagine)的氨基酸来产生天冬氨酸。然而,很少有已知的哺乳动物能够从天冬酰胺中产生天冬氨酸的酶,其中包括豚鼠。

豚鼠天冬酰胺酶的发现

20世纪50年代,一位名叫John Kidd的研究人员有了意外发现。他用各种动物——兔子、马、豚鼠等的血清给身患癌症的小鼠注射,发现光是豚鼠的血清就能缩小鼠的肿瘤。直到几年后,科学家才知道,这种豚鼠血液中的酶,叫做豚鼠天冬酰胺酶1 (gpASNase1 ),具有抗肿瘤作用。今天,我们已经知道了许多具有相似酶的简单生物,包括细菌和斑马鱼。而细菌的天冬酰胺酶(bacterial asparaginase)已被认为是治疗急性淋巴细胞白血病的药物。

由于豚鼠是哺乳动物,具有与我们相似的代谢,因此麻省理工学院的研究人员决定使用gpASNase1来提高四种不同肿瘤中的天冬氨酸水平,并观察肿瘤是否会生长得更快。结果证明,结肠癌细胞、骨肉瘤细胞和小鼠胰腺癌细胞分裂比以前更快,但是人类胰腺癌细胞继续以正常的速度增殖。

Sullivan解释说:“这是一个相对较小的样本,并不是身体的每一个细胞都像其他细胞一样对天冬氨酸敏感。获取天冬氨酸可能只是部分癌症的代谢限制(a metabolic limitation),因为天冬氨酸可以通过多种不同途径产生,而非仅仅通过天冬酰胺的转化。”

当研究人员试图用抗糖尿病的二甲双胍减缓肿瘤生长时,表达gpASNase1的细胞没有受到影响,这证实了Sullivan先前的怀疑,即二甲双胍通过阻止细胞呼吸和抑制天冬氨酸的产生而特异性减缓肿瘤生长。

“我们最初发现二甲双胍与细胞增殖有关是非常意外的,但这些最新的结果已经给出了清楚的证据。它们显示天冬氨酸水平的降低也降低了一些肿瘤的生长。下一步是确定是否有其他方法来靶向某些组织中天冬氨酸的合成,改进我们目前的治疗方法。"Sullivan说。

重要意义

这些发现表明,针对肿瘤的一种手段是阻止肿瘤获取或产生天冬氨酸等营养物质来制造新细胞。

该研究的通讯作者之一Matthew Vander Heiden认为:“这项研究让我们开始认识到,了解某些癌症患者会对哪些治疗做出反应可能取决于基因突变以外的因素。要真正了解癌症全貌,我们还要考虑肿瘤位置、营养物的可用性及生存环境等。”

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    2018-11-23 sunylz
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    2018-09-02 维他命
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    2019-03-14 liye789132251
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    2018-07-05 yxch36

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