來自英國癌癥研究協(xié)會的科學家發(fā)現(xiàn)如何阻斷一種有助于將葡萄糖轉(zhuǎn)換為能量的關鍵性酶,，從而可能提供一種新方法來殺死前列腺癌細胞,。相關研究結(jié)果于2012年3月22日發(fā)表在Cancer Discovery 期刊上,。

對所有細胞來說，葡萄糖是一種重要的能量來源,。癌細胞要比正常細胞更加快速地發(fā)生分裂,，因此它們消耗更多的葡萄糖。但是這也會觸發(fā)導致DNA損傷的自由基大量積累,。

在這項研究中,，研究人員發(fā)現(xiàn)一種被稱作PFKFB4的酶在平衡這兩種過程中發(fā)揮著關鍵性作用：確保癌細胞的能量需求得到滿足，同時又不允許自由基積累而導致細胞死亡,。

領導這項研究的Almut Schulze博士說,，“在實驗室培養(yǎng)的前列腺癌細胞中阻斷PFKFB4會導致它們停止生長，并觸發(fā)自由基災難性地積累,，這就表明這種酶可能適合作為一種藥物靶標,。重要的是，而且鑒于很多不同類型的癌癥都擁有這種能量產(chǎn)生途徑,，這就表明靶向PFKFB4的藥物可能有潛力被用來治療很多種癌癥?！?/p>

研究人員在實驗室培養(yǎng)的晚期前列腺癌細胞中阻斷了222種參與能量產(chǎn)生的不同類型的酶和其他蛋白,，然后研究了它們的存活情況。他們將研究結(jié)果與健康細胞進行比較以便精確地找出哪些蛋白是這些癌細胞存活所必需的,。

他們鑒定出兩個基因PFKFB4 和PRKAB1：兩者在所有進行分析的三個癌細胞系中都表現(xiàn)出相似的影響,，而且已知在發(fā)生轉(zhuǎn)移的前列腺癌細胞中這兩個基因要比來自原始腫瘤中的那些癌細胞表現(xiàn)出更高的活性。已知在小鼠中,，當其中一個基因失活時,，只有基因PFKFB4失活能夠阻止腫瘤生長。

這項研究強調(diào)癌細胞必須在產(chǎn)生足夠的能量和限制DNA損傷以便生存下來之間維持微妙的平衡,。找到破壞這種平衡的方法將可能為人們在未來開發(fā)出新一代抗癌藥物打下堅實基礎,。(生物谷：towersimper編譯)

doi:10.1158/2159-8290.CD-11-0234
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Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival

Susana Ros, Claudio R. Santos, Sofia Moco, Franziska Baenke, Gavin Kelly, Michael Howell, Nicola Zamboni and Almut Schulze

Alterations in metabolic activity contribute to the proliferation and survival of cancer cells. We investigated the effect of siRNA-mediated gene silencing of 222 metabolic enzymes, transporters, and regulators on the survival of 3 metastatic prostate cancer cell lines and a nonmalignant prostate epithelial cell line. This approach revealed significant complexity in the metabolic requirements of prostate cancer cells and identified several genes selectively required for their survival. Among these genes was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), an isoform of phosphofructokinase 2 (PFK2). We show that PFKFB4 is required to balance glycolytic activity and antioxidant production to maintain cellular redox balance in prostate cancer cells. Depletion of PFKFB4 inhibited tumor growth in a xenograft model, indicating that it is required under physiologic nutrient levels. PFKFB4 mRNA expression was also found to be greater in metastatic prostate cancer compared with primary tumors. Taken together, these results indicate that PFKFB4 is a potential target for the development of antineoplastic agents.
Significance: Cancer cells undergo several changes in their metabolism that promote growth and survival. Using an unbiased functional screen, we found that the glycolytic enzyme PFKFB4 is essential for prostate cancer cell survival by maintaining the balance between the use of glucose for energy generation and the synthesis of antioxidants. Targeting PFKFB4 may therefore present new therapeutic opportunities.

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