PLoS One:乳腺癌细胞转移核心机制终破解

2019-10-08 Paris 转化医学网

密歇根大学癌症研究中心的研究人员发现,乳腺癌细胞储存能量,利用能量代谢来促进生长、扩散和转移,而控制大脑中糖原降解的关键酶PYGB在这一过程中则起到了关键作用。

密歇根大学癌症研究中心的研究人员发现,乳腺癌细胞储存能量,利用能量代谢来促进生长、扩散和转移,而控制大脑中糖原降解的关键酶PYGB在这一过程中则起到了关键作用。

其实早在1927年,德国医生、生理学家和生物化学家奥托·海因里希·瓦尔堡(沃伯格)便正式提出了著名的瓦氏效应(沃伯格效应),他认为癌细胞生长速度远远大于正常细胞的原因来自能量来源差别,癌细胞喜欢利用能量较低的葡萄糖(而非能量较高的脂肪酸)获得能量,并且喜欢通过效率较低的无氧发酵(而非效率较高的有氧呼吸)分解葡萄糖而释放能量。而如果切断癌细胞的能量供应,就有可能阻止癌细胞生长。

近几年关于癌症的研究绝大多数也是围绕着能量代谢,但癌细胞是如何储存糖原的呢?糖原的分解代谢又是如何影响癌症发展呢?这背后的机制依然不得而知。

在乳腺癌中,肿瘤乏氧与预后不良和侵袭性增强增加有关。缺氧激活癌细胞的转录程序,导致其更快速地生长、转移。那么,缺氧与糖原储存是否具有相关性呢?

在本次研究中,研究小组首先检测了三阴乳腺癌、炎性乳腺癌、激素受体阳性乳腺癌以及健康乳腺细胞的糖原水平。

结果发现,糖原水平与乳腺癌细胞增殖速率成反比,不仅如此,缺氧会刺激乳腺癌细胞增加糖原储备。当对所有乳腺癌细胞同时增加糖原储备量来消除缺氧环境的影响时,结果显示,基线规范糖原水平与低痒环境中糖原增加在不同乳腺癌类型中存在巨大差异,其中,炎性乳腺癌细胞的糖原增加量要高于其他类型的10倍之多,这表明,糖原代谢表型在不同乳腺癌类型中表达不同。

进一步探索发现,控制脑内糖原降解的酶--糖原磷酸化酶B(PYGB)在乳腺癌糖原控制中起着关键作用。在糖原分解过程中,糖原磷酸化酶催化糖原的磷酸解作用,使糖原分子从非还原端逐个断开α-1,4-糖苷键移去葡萄糖基,释放1-磷酸葡萄糖,直至临近糖原分子α-1,6-糖苷键分支点前4个葡萄糖基处。而PYGB主要在大脑中表达。

当研究人员靶向去除PYGB时,发现这些细胞无法利用糖原进行能量储存,这意味着乳腺癌细胞进一步的发生发展受到了限制。有趣的是,他们在正常的乳腺细胞中并没有看到同样的效果,因此,乳腺癌细胞特异性利用糖原分解储存能量来供应自身的营养。

Merajver表示,这是从全新的角度来看待乳腺癌细胞,这种改变,对于乳腺癌细胞根据其所处的环境来进行重新布局,或许是许多患者对乳腺癌药物产生耐药性的原因。而PYGB可能是治疗或预防乳腺癌转移新的潜在靶点。未来也计划在动物实验中进一步验证这一机制。研究人员还将研究糖原磷酸化酶抑制剂是否能减缓或阻止癌症的转移,如果顺利,乳腺癌的治疗则将会有质的飞跃!

原始出处:
Altemus MA1,2,3, Goo LE2,3, Little AC2,3, et al.Breast cancers utilize hypoxic glycogen stores via PYGB, the brain isoform of glycogen phosphorylase, to promote metastatic phenotypes.PLoS One. 2019 Sep 19;14(9):e0220973. doi: 10.1371/journal.pone.0220973. eCollection 2019.

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    2019-10-10 yxch36
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    2019-10-10 zz72
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