ISPO

Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Blockade of the extracellular signal-regulated kinase pathway induces marked G1 cell cycle arrest and apoptosis in tumor cells in which the pathway is constitutively activated

R Hoshino PhD, M Kohno PhD

Laboratory of Cell Regulation, School of Pharmaceutical Sciences, Nagasaki University, Nagasaki, Japan, kohnom@net.nagasaki-u.ac.jp

AIMS: Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway is associated with the neoplastic phenotype of a relatively large number of humor tumors; tumor cells derived from pancreas, colon, ovary and kidney tissues show especially high frequencies (30~50%) and high degree of kinase activation. In this report, we have examined the effect of blockade of the ERK pathway on the proliferation of human tumor cells in vitro. METHODS: PD98059, a specific inhibitor of mitogen-activated protein (MAP) kinase/ERK kinase (MEK), was utilized for a specific blockade of the ERK pathway in tumor cells. RESULTS: Blockade of the ERK pathway by treatment with PD98059 completely suppressed the growth of tumor cells in which the pathway is constitutively activated. Consistent with its prominent antiproliferative effect, PD98059 induced marked G1 cell cycle arrest in these cells: selective up-regulation of p27Kip1 was observed after PD98059 treatment. Furthermore, PD98059 induced a modest apoptotic response in these tumor cells, which was revealed by the appearance of condensed and fragmented nuclei and by chromosomal DNA degradation. PD98059 inhibited considerably but not completely the proliferation of tumor cells in which constitutive activation of the ERK pathway is undetectable and in diploid fibroblasts. Importantly, PD98059 caused no increase in the proportion of diploid fibroblasts with fractional DNA content. Moreover, growth-inhibited diploid fibroblasts reinitiated proliferation soon after removal of PD98059. CONCLUSIONS: Our results suggest that the ERK pathway is a potential therapeutic target in tumor cells in which the ERK pathway is constitutively activated.

KEY WORDS: ERK pathway, MEK inhibitor, G1 cell cycle arrest, apoptosis, p27^Kip1.

For more information, contact kohnom@net.nagasaki-u.ac.jp

Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on cell cycle inhibitors.

http://www.cancerprev.org/Journal/Issues/24/101/108/3399