Nature：AMPK酶在癌症中的双重作用

近日，伊利诺伊州芝加哥大学医学院研究人员发现一个既能抑制细胞增殖，同时又能帮助肿瘤起始阶段的肿瘤细胞以及肿瘤细胞转移至其他器官阶段中细胞存活的蛋白分子。这项研究结果发表在5月31日的Nature杂志上。

这项新的研究结果似乎违背先前的研究结论，这项新研究发现AMP活化的蛋白激酶或AMPK的激活酶能抑制肿瘤细胞的生长。
 
生物化学和分子遗传学教授Nissim Hay表示：由于其在抑制癌细胞生长和增殖中的作用，AMPK的已作为一种很有前途的化疗药物潜在靶标。

但Hay和他同事们发现当细胞处于代谢压力下，AMPK的激活会促进细胞的存活，防止细胞死亡。

Hay说：这与先前的研究结果是矛盾的，当葡萄糖摄取减少时，激活的AMPK实际上是癌细胞代谢应激期间生存必须的。当癌细胞起初离开肿瘤细胞外基质到迁移、传播过程中，肿瘤细胞受到代谢压力。

研究人员发现AMPK通过间接调节NADPH促进癌细胞的生存。他们发现，AMPK通过调节控制脂肪酸合成和脂肪酸氧化酶发挥作用。这项新的研究也可能有助于解释先前的意外发现：细胞缺乏AMPK或另一种激活AMPK的酶--LKB1能抑制癌症生长。

这项研究由国立卫生研究院的资助，芝加哥社区信托基金芝加哥生物医学联盟以及芝加哥大学糖尿病研究和培训中心的支持。

doi:10.1038/nature11066
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AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress

Sang-Min Jeon, Navdeep S. Chandel, Nissim Hay

Overcoming metabolic stress is a critical step for solid tumour growth^{1, 2}. However, the underlying mechanisms of cell death and survival under metabolic stress are not well understood. A key signalling pathway involved in metabolic adaptation is the liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK) pathway^{2, 3}. Energy stress conditions that decrease intracellular ATP levels below a certain level promote AMPK activation by LKB1. Previous studies showed that LKB1-deficient or AMPK-deficient cells are resistant to oncogenic transformation and tumorigenesis^{4, 5, 6}, possibly because of the function of AMPK in metabolic adaptation. However, the mechanisms by which AMPK promotes metabolic adaptation in tumour cells are not fully understood. Here we show that AMPK activation, during energy stress, prolongs cell survival by redox regulation. Under these conditions, NADPH generation by the pentose phosphate pathway is impaired, but AMPK induces alternative routes to maintain NADPH and inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1 and ACC2 by AMPK maintains NADPH levels by decreasing NADPH consumption in fatty-acid synthesis and increasing NADPH generation by means of fatty-acid oxidation. Knockdown of either ACC1 or ACC2 compensates for AMPK activation and facilitates anchorage-independent growth and solid tumour formation in vivo, whereas the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions, such as glucose limitations, anchorage-independent growth and solid tumour formation in vivo.