title: Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells.
abstract: 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 DR5 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.
authors: School of Life Sciences, Shandong Provincial Key Laboratory Of Animal Cells and Developmental Biology, Shandong University, Jinan, People's Republic of China.
authors: Ling
authors: L
authors: Su
authors: Guangbo
authors: G
authors: Liu
authors: Xuexi
authors: X
authors: Hao
authors: Ning
authors: N
authors: Zhong
authors: Diansheng
authors: D
authors: Zhong
authors: Xiangguo
authors: X
authors: Liu
authors: Sunil
authors: S
authors: Singhal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D000068437:Pemetrexed; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C497249:DDIT3 protein, human; D005971:Glutamates; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000068437:Pemetrexed; D051742:Transcription Factor CHOP; D006147:Guanine