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The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

Oncogene volume 27, pages 3102–3110 (2008)Cite this article

Abstract

PKC412 is a staurosporine derivative that inhibits several protein kinases including FLT3, and is highly anticipated as a novel therapeutic agent for acute myeloblastic leukemia (AML) carrying FLT3 mutations. In this study, we show that PKC412 exerts differential cell cycle effects on AML cells depending on the presence of FLT3 mutations. PKC412 elicits massive apoptosis without markedly affecting cell cycle patterns in AML cell lines with FLT3 mutations (MV4-11 and MOLM13), whereas it induces G2 arrest but not apoptosis in AML cell lines without FLT3 mutations (THP-1 and U937). In MV4-11 and MOLM13 cells, PKC412 inactivates Myt-1 and activates CDC25c, leading to the activation of CDC2. Activated CDC2 phosphorylates Bad at serine-128 and facilitates its translocation to the mitochondria, where Bad triggers apoptosis. In contrast, PKC412 inactivates CDC2 by inducing serine-216 phosphorylation and subsequent cytoplasmic sequestration of CDC25c in THP-1 and U937 cells. As a result, cells are arrested in the G2 phase of the cell cycle, but do not undergo apoptosis because Bad is not activated. The FLT3 mutation-dependent differential cell cycle effect of PKC412 is considered an important factor when PKC412 is combined with cell cycle-specific anticancer drugs in the treatment of cancer and leukemia.

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Acknowledgements

This work was supported in part by the High-Tech Research Center Project for Private Universities: Matching Fund Subsidy from MEXT 2002–2006, and grants from the Vehicle Racing Commemorative Foundation and Sankyo Foundation of Life Science (to YF). JK is a winner of the Jichi Medical School Young Investigator Award. TW is a winner of the Jichi Medical School Graduate Student Award.

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Authors and Affiliations

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

    T Odgerel, J Kikuchi, T Wada, R Shimizu, K Futaki & Y Furukawa

  2. Division of Hematology, Tochigi Cancer Center, Tochigi, Japan

    Y Kano

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  1. T Odgerel
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  2. J Kikuchi
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  3. T Wada
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  4. R Shimizu
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  5. K Futaki
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  6. Y Kano
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  7. Y Furukawa
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Correspondence to Y Furukawa.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Odgerel, T., Kikuchi, J., Wada, T. et al. The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations. Oncogene 27, 3102–3110 (2008). https://doi.org/10.1038/sj.onc.1210980

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