The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition

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  • Ryo Ishida
    1Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.
  • Michiyo Koyanagi-Aoi
    1Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.
  • Nobu Oshima
    5Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • Yoshihiro Kakeji
    3Division of Gastro-intestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan.
  • Takashi Aoi
    1Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.

書誌事項

公開日
2017-10-01
資源種別
journal article
DOI
  • 10.1158/1541-7786.mcr-17-0071
公開者
American Association for Cancer Research (AACR)

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説明

<jats:title>Abstract</jats:title> <jats:p>Cancer stem cells (CSC) are capable of reconstructing cancer tissues, are involved in both recurrence and metastasis, and contribute to therapeutic resistance. Therefore, elucidating the molecular mechanism in CSCs is important to successfully treat unresectable cancers. Previously, we observed that colon cancer stem-like cells can be induced from human colon cancer cell lines by retrovirally introducing OCT3/4, SOX2, and KLF4, and we have designated such cells as induced cancer stem cells (iCSC). In the current study, we used iCSCs to evaluate the molecular mechanism of colon CSCs and developed new methods to control them. The spheres that were derived in vitro from the iCSCs, but not those from parental cells, mimicked human colon cancer tissues in terms of their immunohistologic patterns; therefore, sphere-forming ability was assessed as a measure of the tissue-reconstructing ability of iCSCs. Interestingly, the calcineurin inhibitor FK506 enhanced the sphere-forming ability of iCSCs, whereas GSK3 inhibition by RNAi, CHIR99021, and valproic acid (VPA) impeded the sphere-forming ability and expansion of iCSCs. FK506 and GSK3 inhibition showed the opposite effect regarding the NFATc3 localization of iCSCs. These data reveal the crucial role that NFAT localization, as regulated by calcineurin and GSK3, plays in the tissue-reconstructing ability of colon cancer stem cells and the potential of GSK3 inhibitors, such as VPA, in colon cancer stem cell–targeting therapy.</jats:p> <jats:p>Implications: This study identifies signaling pathways that contribute to the tissue-reconstructing capacity of colon CSCs and suggests that clinically used drugs could be repurposed to improve unresectable colon cancers. Mol Cancer Res; 15(10); 1455–66. ©2017 AACR.</jats:p>

収録刊行物

  • Molecular Cancer Research

    Molecular Cancer Research 15 (10), 1455-1466, 2017-10-01

    American Association for Cancer Research (AACR)

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