Salani Barbara, Ravera Silvia, Amaro Adriana, Salis Annalisa, Passalacqua Mario, Millo Enrico, Damonte Gianluca, Marini Cecilia, Pfeffer Ulrich, Sambuceti Gianmario, Cordera Renzo, Maggi Davide
a Department of Internal Medicine (DIMI) ; University of Genova ; Genova , Italy.
Cell Cycle. 2015;14(10):1559-67. doi: 10.1080/15384101.2015.1026490.
Pyruvate kinase M2 (PKM2) acts at the crossroad of growth and metabolism pathways in cells. PKM2 regulation by growth factors can redirect glycolytic intermediates into key biosynthetic pathway. Here we show that IGF1 can regulate glycolysis rate, stimulate PKM2 Ser/Thr phosphorylation and decrease cellular pyruvate kinase activity. Upon IGF1 treatment we found an increase of the dimeric form of PKM2 and the enrichment of PKM2 in the nucleus. This effect was associated to a reduction of pyruvate kinase enzymatic activity and was reversed using metformin, which decreases Akt phosphorylation. IGF1 induced an increased nuclear localization of PKM2 and STAT3, which correlated with an increased HIF1α, HK2, and GLUT1 expression and glucose entrapment. Metformin inhibited HK2, GLUT1, HIF-1α expression and glucose consumption. These findings suggest a role of IGFIR/Akt axis in regulating glycolysis by Ser/Thr PKM2 phosphorylation in cancer cells.
丙酮酸激酶M2（PKM2）作用于细胞生长和代谢途径的交叉点。生长因子对PKM2的调节可将糖酵解中间体重定向到关键的生物合成途径。在此我们表明，胰岛素样生长因子1（IGF1）可调节糖酵解速率，刺激PKM2的丝氨酸/苏氨酸磷酸化并降低细胞丙酮酸激酶活性。在IGF1处理后，我们发现PKM2的二聚体形式增加且PKM2在细胞核中富集。这种效应与丙酮酸激酶酶活性的降低相关，并且使用二甲双胍可逆转这种效应，二甲双胍可降低Akt磷酸化。IGF1诱导PKM2和信号转导及转录激活因子3（STAT3）的核定位增加，这与缺氧诱导因子1α（HIF1α）、己糖激酶2（HK2）和葡萄糖转运蛋白1（GLUT1）表达增加以及葡萄糖滞留相关。二甲双胍抑制HK2、GLUT1、HIF - 1α表达和葡萄糖消耗。这些发现表明IGF1受体/Akt轴在癌细胞中通过丝氨酸/苏氨酸PKM2磷酸化调节糖酵解中发挥作用。
