ZD1839 induces p15INK4b and causes G1 arrest by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway.
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(1) 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.
Koyama
Makoto
M
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Matsuzaki
Youichirou
Y
Yogosawa
Shingo
S
Hitomi
Toshiaki
T
Kawanaka
Mayumi
M
Sakai
Toshiyuki
T
D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D050762:Cyclin-Dependent Kinase Inhibitor p15; D005419:Flavonoids; D011799:Quinazolines; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one