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Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2

机译：胰岛素通过糖酵解丙酮酸激酶M2的双重调控增强癌细胞的代谢能力

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Background Insulin is tightly associated with cancer progression; however, mechanistic insights into such observations are poorly understood. Recent studies show that metabolic transformation is critical to cancer cell proliferation. Here, we attempt to understand the role of insulin in promotion of cancer metabolism. To this end, the role of insulin in regulating glycolytic enzyme pyruvate kinase M2 (PKM2) was examined. Results We observed that insulin up-regulated PKM2 expression, through PI3K / mTOR mediated HIF1α induction, but significantly reduced PKM2 activity independent of this pathway. Drop in PKM2 activity was attributed to subunit dissociation leading to formation of low activity PKM2 oligomers, as assessed by density gradient centrifugation. However, tyrosine 105 phosphorylation of PKM2, known for inhibiting PKM2 activity, remained unaffected on insulin treatment. Interestingly, insulin-induced ROS was found responsible for PKM2 activity reduction. The observed changes in PKM2 status led to augmented cancer metabolism. Insulin-induced PKM2 up-regulation resulted in enhanced aerobic glycolysis as confirmed by PKM2 knockdown studies. Further, PKM2 activity reduction led to characteristic pooling of glycolytic intermediates and increased accumulation of NADPH; suggesting diversion of glucose flux towards macromolecular synthesis, necessary for cancer cell growth. Conclusion The study identifies new PKM2-mediated effects of insulin on cancer metabolism, thus, advancing the understanding of insulin’s role in cancer.
机译：背景技术胰岛素与癌症进展密切相关。但是，对这种观察的机械见解知之甚少。最近的研究表明，代谢转化对于癌细胞的增殖至关重要。在这里，我们试图了解胰岛素在促进癌症新陈代谢中的作用。为此，检查了胰岛素在调节糖酵解丙酮酸激酶M2（PKM2）中的作用。结果我们观察到，胰岛素通过PI3K / mTOR介导的HIF1α诱导上调了PKM2的表达，但显着降低了PKM2的活性，而与该途径无关。 PKM2活性下降归因于亚基解离，导致低活性PKM2低聚物的形成，如密度梯度离心法所评估。然而，已知抑制PKM2活性的PKM2的酪氨酸105磷酸化在胰岛素治疗中不受影响。有趣的是，发现胰岛素诱导的ROS导致PKM2活性降低。观察到的PKM2状态变化导致癌症代谢增加。胰岛素诱导的PKM2上调导致增强的有氧糖酵解，如PKM2敲低研究所证实。此外，PKM2活性的降低导致糖酵解中间体的特征性合并和NADPH积累的增加;提示葡萄糖流向癌细胞合成所必需的大分子合成转移。结论该研究确定了新的PKM2介导的胰岛素对癌症代谢的作用，从而增进了对胰岛素在癌症中作用的认识。

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