PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells.
PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells.
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DOI：
10.1016/j.cellsig.2010.05.006
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发表时间：
2010-09
影响因子：
4.8
通讯作者：
Kiyatkin A
中科院分区：
文献类型：
--
作者：
Aksamitiene E;Kholodenko BN;Kolch W;Hoek JB;Kiyatkin A
我们探讨了细胞存活（磷脂酰肌醇3-激酶（PI 3 K）/Akt）和促有丝分裂（Ras/Raf/MEK/细胞外信号调节激酶（ERK））信号通路之间的串扰激活的表皮生长因子（EGF），并分析了它们的敏感性PI 3 K突变雌激素受体（ER）阳性MCF 7和T47 D乳腺癌细胞的小分子抑制剂。与MCF 7细胞相比，T47 D细胞中的ERK磷酸化对几种结构不同的化合物（如U 0126、PD 098059和PD 198306）的MEK抑制、小干扰RNA（siRNA）的MEK抑制表现出抗性，并且对渥曼青霉素的PI 3 K抑制也不太敏感。在PI 3 K-野生型ER-阳性BT-474细胞中观察到类似的效果，尽管程度小得多。MEK非依赖性ERK激活仅由ErbB受体配体诱导，并且对已知参与Ras/促分裂原活化蛋白激酶（MAPK）级联调节的几种激酶和磷酸酶的抑制具有抗性。尽管针对PDK 1或Akt的单一药物不影响EGF诱导的ERK磷酸化，但PI 3 K/Akt和MEK抑制剂的组合协同抑制ERK活化和细胞生长。siRNA介导的I类PI 3 K或Akt 1/2基因沉默也显著降低了U 0126抗性ERK磷酸化。我们的数据表明，在T47 D细胞ErbB家族配体诱导一个动态的，PI 3 K/Akt敏感的和MEK独立的补偿ERK激活电路，这是在MCF 7细胞中不存在。我们讨论了可能参与这种激活电路的候选蛋白，并建议PDZ结合激酶/T-LAK细胞来源的蛋白激酶（PBK/TOPK）可能在介导MEK独立的ERK激活中发挥作用。
We explored the crosstalk between cell survival (phosphatidylinositol 3-kinase (PI3K)/Akt) and mitogenic (Ras/Raf/MEK/extracellular signal-regulated kinase (ERK)) signaling pathways activated by an epidermal growth factor (EGF) and analyzed their sensitivity to small molecule inhibitors in the PI3K-mutant estrogen receptor (ER)-positive MCF7 and T47D breast cancer cells. In contrast to MCF7 cells, ERK phosphorylation in T47D cells displayed resistance to MEK inhibition by several structurally different compounds, such as U0126, PD 098059 and PD 198306, MEK suppression by small interfering RNA (siRNA) and was also less sensitive to PI3K inhibition by wortmannin. Similar effect was observed in PI3K-wild type ER-positive BT-474 cells, albeit to a much lesser extent. MEK-independent ERK activation was induced only by ErbB receptor ligands and was resistant to inhibition of several kinases and phosphatases that are known to participate in the regulation of Ras/mitogen-activated protein kinase (MAPK) cascade. Although single agents against PDK1 or Akt did not affect EGF-induced ERK phosphorylation, a combination of PI3K/Akt and MEK inhibitors synergistically suppressed ERK activation and cellular growth. siRNA-mediated silencing of class I PI3K or Akt1/2 genes also significantly decreased U0126-resistant ERK phosphorylation. Our data suggest that in T47D cells ErbB family ligands induce a dynamic, PI3K/Akt-sensitive and MEK-independent compensatory ERK activation circuit that is absent in MCF7 cells. We discuss candidate proteins that can be involved in this activation circuitry and suggest that PDZ-Binding Kinase/T-LAK Cell-Originated Protein Kinase (PBK/TOPK) may play a role in mediating MEK-independent ERK activation.
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