The Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2598-603. doi: 10.1073/pnas.0914018107. Epub 2010 Jan 20.
Phosphotidylinositol-3-kinase (PI3K) signaling is altered in the majority of human cancers. To gain insight into the roles of members of this pathway in growth regulation, we inactivated AKT1, AKT2, or PDPK1 genes by targeted homologous recombination in human colon cancer cell lines. Knockout of either AKT1 or AKT2 had minimum effects on cell growth or downstream signaling. In contrast, knockout of both AKT1 and AKT2 resulted in markedly reduced proliferation in vitro when growth factors were limiting and severely affected experimental metastasis in mice. Unexpectedly, AKT1 and AKT2 appeared to regulate growth through FOXO proteins, but not through either GSK3beta or mTOR. In contrast, inactivation of PDPK1 affected GSK3beta and mTOR activation. These findings show that the PI3K signaling pathway is wired differently in human cancer cells than in other cell types or organisms, which has important implications for the design and testing of drugs that target this pathway.
磷酸肌醇-3-激酶（PI3K）信号在大多数人类癌症中发生改变。为了深入了解该通路成员在生长调控中的作用，我们通过靶向同源重组在人结肠癌细胞系中敲除 AKT1、AKT2 或 PDPK1 基因。敲除 AKT1 或 AKT2 对细胞生长或下游信号几乎没有影响。相比之下，当生长因子有限时，敲除 AKT1 和 AKT2 会导致体外增殖明显减少，并严重影响小鼠的实验性转移。出乎意料的是，AKT1 和 AKT2 似乎通过 FOXO 蛋白而不是 GSK3β 或 mTOR 来调节生长。相比之下，PDPK1 的失活会影响 GSK3β 和 mTOR 的激活。这些发现表明，PI3K 信号通路在人类癌细胞中的作用方式与其他细胞类型或生物体不同，这对设计和测试针对该通路的药物具有重要意义。
