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Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c

Oncogene volume 22, pages 4074–4082 (2003)Cite this article

Abstract

ARG is a tyrosine kinase closely related to ABL, which is oncogenic when fused to the transcriptional repressor ETV6 (ETS translocation variant 6). In this study, we investigated the growth-inhibitory effect of STI571 (signal transduction inhibitor number 571) on ETV6/ARG-expressing cells and its molecular mechanisms using HT93A, a cell line derived from a patient with AML-M3 carrying t(1;12). STI571 effectively suppressed overall tyrosyl phosphorylation of intracellular proteins including ETV6/ARG fusion protein, as well as the growth of HT93A cells with an IC50 of 200 nM. The growth inhibition was primarily because of cell cycle arrest at G1 phase when cells were treated with 100 nM STI571 for 48 h, and apoptosis was induced after longer exposure (72 h) or by a higher dose (1000 nM). STI571 increased the amount of p18/INK4c after 2 h of culture, when the cell cycle pattern was not yet affected, but not that of other CDK inhibitors (CKI). p18/INK4c was more abundant in G1-enriched fractions than in S- and G2/M-enriched fractions of STI571-treated HT93A cells, suggesting that the upregulation of p18/INK4c expression correlates with the cell cycle arrest. Treatment of HT93A cells with antisense oligonucleotides against the Ink4c gene abrogated the growth inhibition by STI571. These results suggest that leukemogenesis by an aberrant ARG kinase involves the suppression of p18/INK4c, which is ubiquitously expressed and considered the major CKI in hematopoietic stem cells. STI571 can be an effective drug for the treatment of leukemias with deregulated ARG kinase activity.

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Acknowledgements

This work was Supported in part by grants-in-aid for Scientific Research (C) from the Ministry of Education, Science and Culture of Japan, and by the Japan Leukemia Research Fund.

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Authors and Affiliations

  1. Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, 329-0498, Japan

    Noriko Nishimura, Yusuke Furukawa, Krittaya Sutheesophon & Mitsuru Nakamura

  2. Department of Hematology and Rheumatology, Tokai University School of Medicine, Kanagawa, 259-1193, Japan

    Kenji Kishi

  3. Department of Hygiene, Kyoto Prefectural University of Medicine, Kyoto, 602-0841, Japan

    Keiko Okuda

  4. Division of Molecular Cytogenetics, International Medical Center of Japan, Tokyo, 162-0052, Japan

    Yuko Sato

  5. Division of Medical Oncology, Tochigi Cancer Center, Tochigi, 320-0834, Japan

    Yasuhiko Kano

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  1. Noriko Nishimura
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Correspondence to Yusuke Furukawa.

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Nishimura, N., Furukawa, Y., Sutheesophon, K. et al. Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c. Oncogene 22, 4074–4082 (2003). https://doi.org/10.1038/sj.onc.1206498

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