• Open Access

Identification of drug candidate against prostate cancer from the aspect of somatic cell reprogramming

Authors

  • Takeo Kosaka,

    1. Department of Urology, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan
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    • These authors contributed equally to this work.
  • Go Nagamatsu,

    Corresponding author
    1. Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan
    2. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan
    • Department of Urology, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan
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    • These authors contributed equally to this work.
  • Shigeru Saito,

    1. Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
    2. Chem and Bio Informatics Department, INFOCOM Corporation, Tokyo, Japan
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    • These authors contributed equally to this work.
  • Mototsugu Oya,

    1. Department of Urology, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan
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  • Toshio Suda,

    Corresponding author
    1. Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan
    • Department of Urology, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan
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  • Katsuhisa Horimoto

    Corresponding author
    1. Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
    • Department of Urology, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan
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To whom correspondence should be addressed.

E-mails: gonag@z2.keio.jp; sudato@z3.keio.jp; k.horimoto@aist.go.jp

Abstract

Considering the similarities between the transcriptional programming involved in cancer progression and somatic cell reprogramming, we tried to identify drugs that would be effective against malignant cancers. We used the early transposon Oct4 and Sox2 enhancer (EOS) system to select human prostate cancer (PCA) cells expressing high levels of OCT4. Patients with metastatic castration-resistant PCA that does not respond to treatment with docetaxel have few therapeutic options. The OCT4-expressing PCA cells selected using the EOS system showed increased tumorigenicity and high resistance to docetaxel, both in vitro and in vivo. By using their gene expression data, expression signature-based prediction for compound candidates identified an antiviral drug, ribavirin, as a conversion modulator from drug resistance to sensitivity. Treatment of PCA cells with ribavirin decreased their resistance against treatment with docetaxel. This indicated that ribavirin reversed the gene expression, including that of humoral factors, in the OCT4-expressing PCA cells selected using the EOS system. Thereby, ribavirin increased the efficacy of docetaxel for cancer cells. We propose a novel cell reprogramming approach, named drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs.

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