GEE-CHEN CHANGKUN-CHIEH CHEN2026-10-162026-10-162011-08-01Pure ID: 15480591Pure UUID: ce25f62a-dc56-404d-bfc6-abbbc127693c10.1016/j.ejphar.2011.04.057https://www.scopus.com/pages/publications/79959287068https://scholars.csmu.edu.tw/handle/123456789/25044Pemetrexed, 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.10enjournal article