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胰腺癌（pancreatic cancer）是最致命且难治的癌症之一，生存率极低，因此被称为“癌中之王”。科学家们一直在寻找胰腺癌中能够被利用的弱点。癌症研究的新策略之一就是研究癌细胞和正常细胞之间的代谢差异，以夺去肿瘤的动力燃料。
近日，来自哈佛医学院达纳-法伯癌症研究所 （Dana-Farber Cancer Institute）的一项最新研究发现，胰腺癌细胞的生长和扩散是通过一条不同寻常的代谢信号通路供给动力，这一发现将有助于促使开发出靶向性药物阻断这一信号通路，从而控制致命性的癌症。相关论文刊登在近期出版的《Nature》上。
众所周知，癌细胞能够以不同于正常细胞的机制，“重新连接”它们的代谢回路为癌性生长提供能源。这项最新研究揭示了胰腺癌细胞通过没有明显备份系统的一条分子信号通路，利用了一种称作谷氨酰胺的氨基酸。研究表明，胰腺癌中发生的“标志”遗传突变——癌基因KARA，引导了代谢重连接，造成了肿瘤对于这一谷氨酰胺信号的依赖。KRAS改变了维持这一信号的关键酶的表达。
研究人员表示，胰腺癌细胞让自身陷入了一个代谢瓶颈。研究表明，如果找到某种方法抑制这条通路上的任何一种酶，癌细胞无法有效补偿，它们则不能继续生长。此外，胰腺癌中这一新谷氨酰胺通路似乎对于正常细胞并不重要，这表明抑制剂可以阻断癌细胞生长，且不会伤害健康的组织和器官。
为了生长，细胞必须防止有害氧自由基累积，它们通过维持一种化学“氧化还原平衡”来做到这一点。研究人员发现，当他们阻断这一谷氨酰胺信号通路中几种酶反应中的任何一种时，可以破坏氧化还原平衡，抑制移植到小鼠体内的人类胰腺癌细胞生长。
研究人员计划下一步开发针对这一谷氨酰胺信号通路的酶抑制剂，它们或许能使得胰腺癌对于放疗和化疗等标准治疗更加的敏感，导致自由基在癌细胞中累积。
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Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway
& t! I2 T9 {$ e- D5 {1 ~5 wNature, 27 March 2013 | doi:10.1038/nature12040
Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.
http://www.bio360.net/news/show/4439.html
发表于 2013-4-1 11:35
