期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 663, 期 1-3, 页码 17-26出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2011.04.057
关键词
Pemetrexed; S phase arrest; Apoptosis; ERK; CDK2; Cyclin-A
资金
- Taichung Veterans General Hospital [TCVGH993204D, TCVGH-997319D]
- National Science Council (Taiwan) [NSC98-3112-B-075A-001, TGHUST99-G7-3, NSC96-2314-b-017-MY3]
Pemetrexed, a multitargeted antifolate with the ability to inhibit several enzymes involved in purine and pyrimidine syntheses, has demonstrated clinical activity in non-small cell lung cancer cells, as well as in a broad array of other solid tumors. In this study, we show that inducing cell cycle S-phase arrest and apoptosis in human lung adenocarcinoma A549 cells with pemetrexed is associated with increased cyclin-A and cyclin-dependent kinase 2 (Cdk2) protein and Cdk2/cyclin-A kinase activity. Knockdown of cyclin-A using small interfering RNA (siRNA), and inhibiting Cdk2 activity with flavopiridol, strikingly reduced S-phase arrest and apoptosis. Moreover, pemetrexed induced sustained activation of extracellular signal-regulated kinase1/2 (ERK1/2). Knockdown of ERK1/2 using specific siRNA, as well as known inhibitors (PD98059 and U0126), effectively suppressed the expression of cyclin-A and Cdk2, and reduced S-phase arrest and apoptosis induced by pemetrexed. These data provide the first evidence that pemetrexed-induced S-phase arrest and apoptosis is associated with an increase in Cdk2 and cyclin-A expression and activation, which is ERK-dependent and upstream of caspase-3. Our findings suggest that the ERK-mediated Cdk2/cyclin-A signaling pathway is an important regulator of pemetrexed-induced S-phase arrest and apoptotic cell death. (C) 2011 Elsevier B.V. All rights reserved.
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