Rice Pamela L, Beard K Scott, Driggers Linda J, Ahnen Dennis J
Veterans Administration Medical Center, Department of Medicine, University of Colorado Health Sciences Center, and University of Colorado Comprehensive Cancer Center, Denver, Colorado 80262, USA.
Cancer Res. 2004 Nov 15;64(22):8148-51. doi: 10.1158/0008-5472.CAN-04-1517.
Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac have shown potent chemopreventive and tumor regressive effects against colorectal cancer, the second leading cause of cancer death in the United States. However, the mechanisms by which sulindac inhibits tumor cell growth are not completely understood. We previously reported that sulindac metabolites inhibit the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascade in colorectal cancer cell lines at doses that induce apoptosis, and inhibition of MEK/ERK activity with U0126 is sufficient to induce apoptotic cell death. To determine whether inhibition of MEK/ERK activity is necessary for sulindac-induced apoptosis of human colon cancer cells, stable transfectants were created that express an activated MEK1 gene in HT29 cells. HT29-MEK1(R4F) clones displayed a 10- to 20-fold increase in MEK1 activity compared with control HT29-pCEP4 clones. When compared with control HT29-pCEP4 clones, HT29-MEK1(R4F) clones were resistant to both apoptosis and inhibition of ERK1/2 phosphorylation induced by sulindac metabolites. These results suggest that inhibition of MEK/ERK signaling is necessary for the induction of apoptosis by sulindac metabolites.
包括舒林酸在内的非甾体抗炎药（NSAIDs）已显示出对结直肠癌具有强大的化学预防和肿瘤消退作用，结直肠癌是美国癌症死亡的第二大主要原因。然而，舒林酸抑制肿瘤细胞生长的机制尚未完全明确。我们之前报道过，舒林酸代谢产物在诱导凋亡的剂量下可抑制结直肠癌细胞系中的丝裂原活化蛋白/细胞外信号调节激酶激酶/细胞外信号调节激酶（MEK/ERK）信号级联反应，并且用U0126抑制MEK/ERK活性足以诱导凋亡性细胞死亡。为了确定抑制MEK/ERK活性对于舒林酸诱导人结肠癌细胞凋亡是否必要，我们构建了在HT29细胞中表达活化MEK1基因的稳定转染子。与对照HT29-pCEP4克隆相比，HT29-MEK1（R4F）克隆的MEK1活性增加了10至20倍。与对照HT29-pCEP4克隆相比，HT29-MEK1（R4F）克隆对舒林酸代谢产物诱导的凋亡和ERK1/2磷酸化抑制均具有抗性。这些结果表明，抑制MEK/ERK信号传导对于舒林酸代谢产物诱导凋亡是必要的。
