School of Life Sciences, Shandong Provincial Key Laboratory Of Animal Cells and Developmental Biology, Shandong University, Jinan, People's Republic of China.
Eur J Cancer. 2011 Nov;47(16):2471-8. doi: 10.1016/j.ejca.2011.06.003. Epub 2011 Jul 2.
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.
培美曲塞是一种临床上可应用的抗叶酸治疗药物，与顺铂联合用于治疗恶性胸膜间皮瘤和晚期非小细胞肺癌患者。培美曲塞抑制嘧啶和嘌呤合成中三个必需的酶，这些酶对于前体 DNA 核苷酸至关重要，从而破坏正常和癌细胞的生长和存活。培美曲塞诱导细胞凋亡的机制在很大程度上尚未阐明。在本研究中，我们研究了培美曲塞在诱导肺癌细胞凋亡中的下游作用。我们发现，培美曲塞通过上调肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）的重要死亡受体 5（DR5）诱导细胞凋亡。此外，我们发现培美曲塞与重组 TRAIL 联合使用具有协同诱导凋亡的作用。通过小干扰 RNA 调节 DR5 的诱导作用，可消除培美曲塞诱导细胞凋亡的能力。此外，沉默 C/EBP 同源蛋白（CHOP）的表达降低了 DR5 的表达，表明转录因子 CHOP 在培美曲塞治疗后 DR5 的上调中具有关键作用。此外，细胞型 Fas 相关死亡结构域蛋白（c-FLIP）的强制表达，作为 caspase 8 的已知抑制剂，可保护肿瘤细胞免受凋亡，尽管接受了培美曲塞和/或 TRAIL 治疗。因此，我们的研究结果表明了培美曲塞诱导细胞凋亡的疗效和机制基础，并表明培美曲塞与 TRAIL 联合使用可能对肺癌患者具有临床应用价值。
