Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival
Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival
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DOI：
10.1158/2159-8290.cd-11-0234
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发表时间：
2012-04-01
期刊：
影响因子：
28.2
通讯作者：
Schulze, Almut
中科院分区：
文献类型：
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作者：
Ros, Susana;Santos, Claudio R.;Schulze, Almut
代谢活动的改变有助于癌细胞的增殖和存活。我们研究了由siRNA介导的222种代谢酶、转运蛋白和调节因子的基因沉默对3个转移性前列腺癌细胞系和1个非恶性前列腺上皮细胞系生存的影响。这一方法揭示了前列腺癌细胞代谢需求的显著复杂性，并确定了几个选择性地需要它们生存的基因。这些基因包括6-phosphofructo-2-kinase/fructose-2，6-biphosphatase 4(PFKFB4)，它是磷酸果糖激酶2(PFK2)的一种异构体。我们发现，在前列腺癌细胞中，PFKFB4需要平衡糖酵解活性和抗氧化剂的产生，以维持细胞氧化还原平衡。在异种移植模型中，PFKFB4的缺失抑制了肿瘤的生长，表明它在生理营养水平下是必需的。转移性前列腺癌组织中PFKFB4的表达水平也高于原发癌。综上所述，这些结果表明PFKFB4是一个潜在的抗肿瘤药物开发的靶点。标志：癌细胞在其代谢过程中经历了几个促进生长和存活的变化。使用无偏见的功能筛选，我们发现糖酵解酶PFKFB4通过维持利用葡萄糖生成能量和合成抗氧化剂之间的平衡，对前列腺癌细胞的生存至关重要。因此，靶向PFKFB4可能会带来新的治疗机会。癌症发现；2(4)；328-43。(C)2012年AACR。
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. Cancer Discov; 2(4); 328-43. (c) 2012 AACR.