Growth factors can influence cell growth and survival through effects on glucose metabolism
Growth factors can influence cell growth and survival through effects on glucose metabolism
复制标题
DOI：
10.1128/mcb.21.17.5899-5912.2001
复制
发表时间：
2001-09-01
影响因子：
5.3
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Vander Heiden, MG;Plas, DR;Thompson, CB
来自多细胞生物体的细胞依赖于外源信号来生存、生长和增殖。使用白细胞介素 3 (IL-3) 依赖性细胞系检查这三个过程之间的关系。 IL-3 没有固定剂量来确定细胞凋亡的阈值。相反，增加生长因子浓度会导致细胞周期 G(1) 期逐渐缩短和更快的增殖扩张。生长因子浓度的增加也导致糖酵解速率成比例增加。矛盾的是，在高浓度生长因子中生长的细胞在生长因子撤除后对细胞死亡的敏感性增加。这种敏感性与生长因子停用后糖酵解速率的变化幅度相关。为了研究糖酵解产物的可用性的变化是否影响线粒体引发的细胞凋亡，我们通过操纵培养基中的葡萄糖水平人为地限制糖酵解。与生长因子撤除一样，葡萄糖限制导致 Bax 易位、线粒体膜电位降低以及细胞色素 c 重新分布到细胞质中。相比之下，通过过度表达 Glut1 来增加细胞自主葡萄糖摄取，可显着延迟生长因子撤除后的细胞凋亡。这些数据表明，生长因子的主要功能是调节葡萄糖摄取和代谢，从而维持线粒体稳态并实现细胞生长所需的合成代谢途径。与这一假设一致的是，在生长因子停用后，涉及葡萄糖摄取和糖酵解承诺的三个基因（Glut1、己糖激酶 2 和磷酸果糖激酶 1）的表达迅速下降至几乎不可检测的水平。
Cells from multicellular organisms are dependent upon exogenous signals for survival, growth, and proliferation. The relationship among these three processes was examined using an interleukin-3 (IL-3) -dependent cell line. No fixed dose of IL-3 determined the threshold below which cells underwent apoptosis. Instead, increasing growth factor concentrations resulted in progressive shortening of the G(1) phase of the cell cycle and more rapid proliferative expansion. Increased growth factor concentrations also resulted in proportional increases in glycolytic rates. Paradoxically, cells growing in high concentrations of growth factor had an increased susceptibility to cell death upon growth factor withdrawal. This susceptibility correlated with the magnitude of the change in the glycolytic rate following growth factor withdrawal. To investigate whether changes in the availability of glycolytic products influence mitochondrion-initiated apoptosis, we artificially limited glycolysis by manipulating the glucose levels in the medium. Like growth factor withdrawal, glucose limitation resulted in Bax translocation, a decrease in mitochondrial membrane potential, and cytochrome c redistribution to the cytosol. In contrast, increasing cell autonomous glucose uptake by overexpression of Glut1 significantly delayed apoptosis following growth factor withdrawal. These data suggest that a primary function of growth factors is to regulate glucose uptake and metabolism and thus maintain mitochondrial homeostasis and enable anabolic pathways required for cell growth. Consistent with this hypothesis, expression of the three genes involved in glucose uptake and glycolytic commitment, those for Glut1, hexokinase 2, and phosphofructokinase 1, was found to rapidly decline to nearly undetectable levels following growth factor withdrawal.