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: Ling Su, Guangbo Liu, Xuexi Hao, Ning Zhong, Diansheng Zhong, Xiangguo Liu, Sunil Singhal
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 47 Issue 16 Pg. 2471-8 (Nov 2011) ISSN: 1879-0852 [Electronic] England
• PMID: 21726997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• CASP8 and FADD-Like Apoptosis Regulating Protein
• DDIT3 protein, human
• Glutamates
• Neoplasm Proteins
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Recombinant Proteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Pemetrexed
• Transcription Factor CHOP
• Guanine

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism, pharmacology)
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology)
• Cell Line, Tumor
• Cells, Cultured
• Glutamates (pharmacology)
• Guanine (analogs & derivatives, pharmacology)
• Humans
• Lung Neoplasms (metabolism, pathology)
• Neoplasm Proteins (metabolism)
• Pemetrexed
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism, pharmacology)
• Recombinant Proteins (pharmacology)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Transcription Factor CHOP (metabolism)
• Up-Regulation