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Research Articles: Therapeutics, Targets, and Development

ZD1839 induces p15^INK4b and causes G₁ arrest by inhibiting the mitogen-activated protein kinase/extracellular signal–regulated kinase pathway

Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan

Requests for reprints: Toshiyuki Sakai, Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Phone: 81-75-251-5339; Fax: 81-75-241-0792. E-mail: tsakai{at}koto.kpu-m.ac.jp

Abstract

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 G₁ 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. [Mol Cancer Ther 2007;6(5):1579–1587]

Grant support: Grant-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, and a Grant-in Aid for the Encouragement of Young Scientists from the Japan Society for the Promotion of Science.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Yamaguchi et al., submitted for publication.

Received 12/31/06; accepted 3/15/07.

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