科学家近日发现，调节代谢的小分子活化物质能阻碍肿瘤的生长，近期的《自然—化学生物学》杂志刊登了这一研究。这或将有助于癌症疗法的开发。
在糖酵解过程中，丙酮酸激酶负责实现最后一步代谢过程，即将葡萄糖转化为能量以及对细胞有重要作用的合成代谢物。丙酮酸激酶分两种：PKM1和PKM2，其中PKM1的活性较大，而PKM2转变后的活性能与肿瘤细胞相符合。
Matthew Vander Heiden等人报告了一类与PKM2发生特异结合并促使其产生活性的小分子活化物质通过阻碍肿瘤生长的方式使肿瘤细胞的代谢发生改变。这些活化物质与PKM2中的新发现的位点相结合，使得PKM2对一类负反馈回路产生抗性——该类负反馈回路可使促生长代谢物产生。对PKM2的持续激活会切断肿瘤细胞中合成代谢养分的供应。PKM2的活化物质还能让肿瘤细胞对氧化应激过敏，这引导出了一种潜在新疗法的开发：通过活化PKM2并结合触发氧化应激的方式，实现杀死肿瘤细胞的目的。（生物谷Bioon.com）
doi:10.1038/nchembio.1060
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Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Dimitrios Anastasiou,Yimin Yu,William J Israelsen,Jian-Kang Jiang,Matthew B Boxer,Bum Soo Hong,Wolfram Tempel,Svetoslav Dimov,Min Shen,Abhishek Jha,Hua Yang,Katherine R Mattaini,Christian M Metallo,Brian P Fiske,Kevin D Courtney,Scott Malstrom,Tahsin M Khan,Charles Kung,Amanda P Skoumbourdis,Henrike Veith,Noel Southall,Martin J Walsh,Kyle R Brimacombe,William Leister,Sophia Y Lunt et al.
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.
