ZD1839 induces p15INK4b and causes G1 arrest by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway
| Autor: | Toshiyuki Sakai, Toshiaki Hitomi, Mayumi Kawanaka, Shingo Yogosawa, Youichirou Matsuzaki, Makoto Koyama |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
MAP Kinase Signaling System Antineoplastic Agents Mitogen-activated protein kinase kinase Models Biological Cell Line Tumor Humans ASK1 c-Raf Phosphorylation Extracellular Signal-Regulated MAP Kinases Cell Proliferation Cyclin-Dependent Kinase Inhibitor p15 Flavonoids MAP kinase kinase kinase biology Cyclin-dependent kinase 4 Chemistry Akt/PKB signaling pathway Cyclin-dependent kinase 2 Cell Cycle G1 Phase Gefitinib Cell biology Gene Expression Regulation Neoplastic Oncology biology.protein Cancer research Quinazolines Cyclin-dependent kinase 9 Signal Transduction |
| Zdroj: | Molecular cancer therapeutics. 6(5) |
| ISSN: | 1535-7163 |
| Popis: | Inactivation of the retinoblastoma protein pathway is the most common abnormality in malignant tumors. We therefore tried to detect agents that induce the cyclin-dependent kinase inhibitor p15INK4b and found that ZD1839 (gefitinib, Iressa) could up-regulate p15INK4b expression. ZD1839 has been shown to inhibit cell cycle progression through inhibition of signaling pathways such as phosphatidylinositol 3′-kinase-Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascades. However, the mechanism responsible for the differential sensitivity of the signaling pathways to ZD1839 remains unclear. We here showed that ZD1839 up-regulated p15INK4b, resulting in retinoblastoma hypophosphorylation and G1 arrest in human immortalized keratinocyte HaCaT cells. p15INK4b induction was caused by MAPK/ERK kinase inhibitor (PD98059), but not by Akt inhibitor (SH-6, Akt-III). Moreover, mouse embryo fibroblasts lacking p15INK4b were resistant to the growth inhibitory effects of ZD1839 compared with wild-type mouse embryo fibroblasts. Additionally, the status of ERK phosphorylation was related to the antiproliferative activity of ZD1839 in human colon cancer HT-29 and Colo320DM cell lines. Our results suggest that induction of p15INK4b by inhibition of the MAPK/ERK pathway is associated with the antiproliferative effects of ZD1839. [Mol Cancer Ther 2007;6(5):1579–1587] |
| Databáze: | OpenAIRE |
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