ヨゴサワ　シンゴ   YOGOSAWA Shingo   与五沢　真吾    所属   埼玉医科大学  保健医療学部 臨床検査学科    職種   准教授
論文種別	学術雑誌(原著)
言語種別	英語
査読の有無	査読あり
表題	ZD1839 induces p15(INK4b) and causes G(1) arrest by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway
掲載誌名	正式名：MOLECULAR CANCER THERAPEUTICS ISSNコード：1535-7163/1538-8514
出版社	AMER ASSOC CANCER RESEARCH
巻・号・頁	6(5),1579-1587頁
著者・共著者	Makoto Koyama,Youichirou Matsuzaki,Shingo Yogosawa,Toshiaki Hitomi,Mayurni Kawanaka,Toshiyuki Sakai
発行年月	2007/05
概要	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 p15(INK4b) and found that ZD1839 (gefitinib, Iressa) could up-regulate p15(INK4b) 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 p15(INK4b), resulting in retinoblastoma hypophosphorylation and G, arrest in human immortalized keratinocyte HaCaT cells. p15(INK4b) induction was caused by MAPK/ERK kinase inhibitor (PD98059), but not by Akt inhibitor (SH-6, Akt-III). Moreover, mouse embryo fibroblasts lacking p15(INK4b) 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 p15(INK4b) by inhibition of the MAPK/ERK pathway is associated with the antiproliferative effects of ZD1839.
DOI	10.1158/1535-7163.MCT-06-0814
PMID	17513607