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  • Original Paper
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Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine)

Oncogene volume 21, pages 1727–1738 (2002)Cite this article

Abstract

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a central role in activating the AGC subfamily of protein kinases. In particular, PDK1 plays an important role in the regulation of Akt/PKB survival pathway by phosphorylating Akt on Thr308. Here we show that UCN-01 (7-hydroxystaurosporine), a drug now in clinical trials and with a unique fingerprint pattern, induced dephosphorylation and inactivation of Akt, resulting in the turn-off of the survival signals and the induction of apoptosis. Further analysis revealed that UCN-01-mediated Akt inactivation was caused by inhibiting upstream Akt kinase PDK1 (IC50=33 nM) both in vitro and from cells, but not by suppressing Akt itself or phosphatidylinositide-3-OH kinase. UCN-01-induced PDK1 inhibition was also observed in in vivo murine and human tumor xenografts. Overexpression of active form of Akt diminished the cytotoxic effects of UCN-01, suggesting that UCN-01 may in part exert its cytotoxicity by inhibiting PDK1-Akt survival pathway. Because UCN-01 has already proved to have potent anti-tumor activity in vivo, PDK1-Akt survival pathway is a new, attractive target for cancer chemotherapy.

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Acknowledgements

This study was supported by a special grant for Advanced Research on Cancer and a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank Dr Marcus Thelen for providing the pcDNA3-p110, pcDNA3-p110CAAX, and pcDNA3-p110CAAX-KD (R916P). We also thank Drs Philip Hawkins and Karen Anderson for providing the pCMV3-PDK1. We appreciate Drs S Akinaga and T. Tamaoki of Kyowa Hakko Kogyo for providing UCN-01, UCN-02, and PC-3 xenografts and for valuable discussions.

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  1. Saori Sato and Naoya Fujita: S Sato and N Fujita contributed equally to the work

Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, 113-0032, Japan

    Saori Sato, Naoya Fujita & Takashi Tsuruo

  2. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 170-8455, Japan

    Takashi Tsuruo

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  1. Saori Sato
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  2. Naoya Fujita
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Correspondence to Takashi Tsuruo.

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Sato, S., Fujita, N. & Tsuruo, T. Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21, 1727–1738 (2002). https://doi.org/10.1038/sj.onc.1205225

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