Small molecule activation of PKM2 in cancer cells induces serine auxotrophy.
Small molecule activation of PKM2 in cancer cells induces serine auxotrophy.
复制标题
DOI：
10.1016/j.chembiol.2012.07.021
复制
发表时间：
2012-09-21
影响因子：
--
通讯作者：
Dang L
中科院分区：
文献类型：
--
作者：
Kung C;Hixon J;Choe S;Marks K;Gross S;Murphy E;DeLaBarre B;Cianchetta G;Sethumadhavan S;Wang X;Yan S;Gao Y;Fang C;Wei W;Jiang F;Wang S;Qian K;Saunders J;Driggers E;Woo HK;Kunii K;Murray S;Yang H;Yen K;Liu W;Cantley LC;Vander Heiden MG;Su SM;Jin S;Salituro FG;Dang L
增殖的肿瘤细胞使用有氧糖酵解来支持它们的高代谢需求。矛盾的是，糖酵解的增加往往伴随着活性较低的PKM2异构体的表达，有效地限制了糖酵解的降低。在这里，我们报告发现PKM2激活剂具有独特的变构结合模式。这些化合物如何影响癌细胞的特性揭示了葡萄糖和氨基酸代谢之间意想不到的联系。PKM2的激活导致癌细胞的代谢重新布线，表现为对非必需氨基酸丝氨酸的严重依赖，以维持细胞的持续增殖。通过激活PKM2诱导丝氨酸营养不良，伴随着进入丝氨酸生物合成途径的碳流量减少和高亲和力丝氨酸转运蛋白的表达增加。这些数据支持了PKM2表达赋予癌细胞代谢灵活性以适应营养应激的假设。
Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM2 isoform, effectively constraining lower glycolysis. Here, we report the discovery of PKM2 activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM2 activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the nonessential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM2 activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM2 expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress.
登录
查看更多内容
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：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
7.4
作者：
Fuhrer, Tobias;Heer, Dominik;Zamboni, Nicola
通讯作者：
Zamboni, Nicola
影响因子：
64.8
作者：
Metallo, Christian M.;Gameiro, Paulo A.;Bell, Eric L.;Mattaini, Katherine R.;Yang, Juanjuan;Hiller, Karsten;Jewell, Christopher M.;Johnson, Zachary R.;Irvine, Darrell J.;Guarente, Leonard;Kelleher, Joanne K.;Vander Heiden, Matthew G.;Iliopoulos, Othon;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory
影响因子：
4.8
作者：
Jousse, Celine;Deval, Christiane;Fafournoux, Pierre
通讯作者：
Fafournoux, Pierre