Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2.
Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2.
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DOI：
10.1186/1476-4598-12-72
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发表时间：
2013-07-09
期刊：
影响因子：
37.3
通讯作者：
Bamezai RN
中科院分区：
文献类型：
--
作者：
Iqbal MA;Siddiqui FA;Gupta V;Chattopadhyay S;Gopinath P;Kumar B;Manvati S;Chaman N;Bamezai RN
胰岛素与癌症进展密切相关；然而，对这种观察的机械性洞察知之甚少。最近的研究表明，代谢转化对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代谢中的作用。为此，研究了胰岛素对糖酵解酶丙酮酸激酶M2(PKM2)的调节作用。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，但显著降低了PKM2的活性，而不依赖于这一途径。通过密度梯度离心法评估，PKM2活性的下降归因于亚基的解离导致形成低活性的PKM2寡聚体。然而，抑制PKM2活性的PKM2的酪氨酸105磷酸化在胰岛素治疗中仍然不受影响。有趣的是，胰岛素诱导的ROS被发现与PKM2活性降低有关。观察到的PKM2状态的变化导致了癌症代谢的增强。胰岛素诱导的PKM2上调导致有氧糖酵解增强，PKM2基因敲除研究证实了这一点。此外，PKM2活性的降低导致糖酵解中间产物的特征性聚集和NADPH的积累；这表明葡萄糖流量转向大分子合成，这是癌细胞生长所必需的。这项研究发现了新的PKM2介导的胰岛素对癌症代谢的影响，从而促进了对胰岛素在癌症中作用的理解。
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. 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. The study identifies new PKM2-mediated effects of insulin on cancer metabolism, thus, advancing the understanding of insulin’s role in cancer.
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DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
3.7
作者：
Iqbal MA;Bamezai RN
通讯作者：
Bamezai RN
DOI：
10.1634/theoncologist.2009-0300
发表时间：
2010
期刊：
The oncologist
影响因子：
--
作者：
Hemminki K;Li X;Sundquist J;Sundquist K
通讯作者：
Sundquist K
影响因子：
5
作者：
Coughlin, SS;Calle, EE;Thun, MJ
通讯作者：
Thun, MJ
影响因子：
7.7
作者：
Fierz Y;Novosyadlyy R;Vijayakumar A;Yakar S;LeRoith D
通讯作者：
LeRoith D