标题：Death Receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells
作者：Su, Ling; Liu, Guangbo; Hao, Xuexi; Zhong, Ning; Zhong, Diansheng; Liu, Xiangguo; Singhal, Sunil
作者机构：[Su, Ling; Liu, Guangbo; Liu, Xiangguo] Shandong Univ, Sch Life Sci, Shandong Prov Key Lab Anim Cells & Dev Biol, Jinan 250100, Peoples R China.; [H 更多
通讯作者地址：[Liu, XG]Shandong Univ, Sch Life Sci, Shandong Prov Key Lab Anim Cells & Dev Biol, Room 103,South Bldg,27 Shandananlu Rd, Jinan 250100, Peoples R Chin 更多
来源：EUROPEAN JOURNAL OF CANCER
关键词：Pemetrexed; DR5; c-FLIP; Apoptosis; CHOP; TRAIL
摘要：Pemetrexed is a clinically available anti-folate therapeutic agent used in combination with cisplatin for the management of patients with malignant pleural mesothelioma and advanced non-small cell lung cancer. Pemetrexed inhibits three enzymes in purine and pyrimidine synthesis necessary for precursor DNA nucleotides which in turn disrupts growth and survival of normal and cancer cells. The mechanism by which pemetrexed induces apoptosis remains largely uncharacterised. In the current study, we examined the downstream effect of pemetrexed in inducing apoptosis in lung cancer cells. We showed that pemetrexed induced apoptosis via up-regulation of Death Receptor 5 (DR5), an important death receptor for tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). In addition, we discovered a synergistic effect of combination pemetrexed and recombinant TRAIL in inducing apoptosis. Modulating DRS induction by small interfering RNA abrogated the ability of pemetrexed to induce apoptosis. In addition, silencing of C/EBP homologous protein (CHOP) expression reduced DR5 expression, demonstrating that the transcriptional factor CHOP has a pivotal role on DR5 up-regulation following pemetrexed treatment. In addition, enforced expression of cellular FLICE-inhibitory protein (c-FLIP), a known inhibitor of caspase 8, protected neoplastic cells from apoptosis despite pemetrexed and/or TRAIL therapy. Thus, our findings demonstrate the efficacy and mechanistic underpinnings of pemetrexed-induced apoptosis, and they suggest pemetrexed may have clinical utility when used in combination with TRAIL for the management of patients with lung cancer. (C) 2011 Elsevier Ltd. All rights reserved.