近日,，伊利諾伊州芝加哥大學(xué)醫(yī)學(xué)院研究人員發(fā)現(xiàn)一個既能抑制細(xì)胞增殖，同時(shí)又能幫助腫瘤起始階段的腫瘤細(xì)胞以及腫瘤細(xì)胞轉(zhuǎn)移至其他器官階段中細(xì)胞存活的蛋白分子,。這項(xiàng)研究結(jié)果發(fā)表在5月31日的Nature雜志上,。
這項(xiàng)新的研究結(jié)果似乎違背先前的研究結(jié)論，這項(xiàng)新研究發(fā)現(xiàn)AMP活化的蛋白激酶或AMPK的激活酶能抑制腫瘤細(xì)胞的生長,。
生物化學(xué)和分子遺傳學(xué)教授Nissim Hay表示：由于其在抑制癌細(xì)胞生長和增殖中的作用,，AMPK的已作為一種很有前途的化療藥物潛在靶標(biāo)。
但Hay和他同事們發(fā)現(xiàn)當(dāng)細(xì)胞處于代謝壓力下,，AMPK的激活會促進(jìn)細(xì)胞的存活,，防止細(xì)胞死亡。
Hay說：這與先前的研究結(jié)果是矛盾的,，當(dāng)葡萄糖攝取減少時(shí),，激活的AMPK實(shí)際上是癌細(xì)胞代謝應(yīng)激期間生存必須的。當(dāng)癌細(xì)胞起初離開腫瘤細(xì)胞外基質(zhì)到遷移,、傳播過程中,，腫瘤細(xì)胞受到代謝壓力,。
研究人員發(fā)現(xiàn)AMPK通過間接調(diào)節(jié)NADPH促進(jìn)癌細(xì)胞的生存。他們發(fā)現(xiàn),，AMPK通過調(diào)節(jié)控制脂肪酸合成和脂肪酸氧化酶發(fā)揮作用,。這項(xiàng)新的研究也可能有助于解釋先前的意外發(fā)現(xiàn)：細(xì)胞缺乏AMPK或另一種激活A(yù)MPK的酶--LKB1能抑制癌癥生長。
這項(xiàng)研究由國立衛(wèi)生研究院的資助,，芝加哥社區(qū)信托基金芝加哥生物醫(yī)學(xué)聯(lián)盟以及芝加哥大學(xué)糖尿病研究和培訓(xùn)中心的支持,。（生物谷：Bioon.com）
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 growth1, 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) pathway2, 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 tumorigenesis4, 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.
