Kim Min, Yan Ying, Kortum Robert L, Stoeger Scott M, Sgagias Magdalene K, Lee Kwangmoon, Lewis Robert E, Cowan Kenneth H
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Cancer Res. 2005 May 15;65(10):3986-92. doi: 10.1158/0008-5472.CAN-03-2334.
Kinase suppressor of Ras1 (KSR1) interacts with several mitogen-activated protein (MAP) kinase pathway components, including Raf, MAP/extracellular signal-regulated kinase (ERK) kinase (MEK), and ERK, and acts as a positive regulator of the Ras signaling cascade. Previous studies have shown that exposure of cells to the anticancer agent cisplatin (cis-diamminedichloroplatinum, CDDP) is associated with changes in multiple signal transduction pathways, including c-Jun-NH2-kinase, ERK, and p38 pathways. Moreover, ERK activation has been linked to changes in cell survival following CDDP treatment. In this report, we have examined the effects of KSR1 expression on the sensitivity of cells to CDDP-induced apoptosis. Loss of KSR1 expression in mouse embryo fibroblasts (MEFs) derived from KSR1 knockout mice (KSR-/- MEF) is associated with decreased CDDP-induced ERK activation and increased resistance to CDDP-induced apoptosis compared with wild-type MEFs (KSR+/+ MEF). Furthermore, transduction of KSR-/- MEFs and MCF-7 breast cancer cells with wild-type KSR1 resulted in enhanced ERK activation following CDDP exposure and increased sensitivity to CDDP. In addition, inhibition of ERK activation by exposing MEFs to the MEK1/2-specific inhibitors PD98059 and U0126 protected both KSR+/+ and KSR-/- MEFs cells from CDDP-induced apoptosis. These results indicate that KSR1-mediated regulation of ERK activity represents a novel determinant of CDDP sensitivity of cancer cells.
Ras1激酶抑制因子（KSR1）与多种丝裂原活化蛋白（MAP）激酶信号通路成分相互作用，包括Raf、MAP/细胞外信号调节激酶（ERK）激酶（MEK）和ERK，并作为Ras信号级联反应的正向调节因子发挥作用。先前的研究表明，细胞暴露于抗癌药物顺铂（顺二氯二氨合铂，CDDP）与多种信号转导通路的变化有关，包括c-Jun氨基末端激酶、ERK和p38通路。此外，ERK激活与CDDP处理后细胞存活的变化有关。在本报告中，我们研究了KSR1表达对细胞对CDDP诱导凋亡敏感性的影响。与野生型小鼠胚胎成纤维细胞（KSR+/+ MEF）相比，源自KSR1基因敲除小鼠的小鼠胚胎成纤维细胞（KSR-/- MEF）中KSR1表达缺失与CDDP诱导的ERK激活降低以及对CDDP诱导凋亡的抗性增加有关。此外，用野生型KSR1转导KSR-/- MEF和MCF-7乳腺癌细胞，导致CDDP暴露后ERK激活增强以及对CDDP的敏感性增加。另外，通过将MEF暴露于MEK1/2特异性抑制剂PD98059和U0126来抑制ERK激活，可保护KSR+/+和KSR-/- MEF细胞免受CDDP诱导的凋亡。这些结果表明，KSR1介导的ERK活性调节代表了癌细胞对CDDP敏感性的一个新的决定因素。
