The effectiveness of an anti-human IL-6 receptor monoclonal antibody combined with chemotherapy to target colon cancer stem-like cells

Jin Ying, Masahiko Tsujii, Jumpei Kondo, Yoshito Hayashi, Motohiko Kato, Tomofumi Akasaka, Takuta Inoue, Eri Shiraishi, Tahahiro Inoue, Satoshi Hiyama, Yoshiki Tsujii, Akira Maekawa, Shoichiro Kawai, Tetsuji Fujinaga, Maekawa Araki, Shinichiro Shinzaki, Kenji Watabe, Tsutomu Nishida, Hideki Iijima, Tetsuo Takehara

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Recent studies have demonstrated that cancer stem cells (CSCs) can initiate and sustain tumor growth and exhibit resistance to clinical cytotoxic therapies. Therefore, CSCs represent the main target of anticancer therapy. Interleukin-6 (IL-6) promotes cellular proliferation and drug resistance in colorectal cancer, and its serum levels correlate with patient survival. Therefore, IL-6 and its downstream signaling molecule the signal transducer and activator of transcription-3 (STAT3) represent potential molecular targets. In the present study, we investigated the effects of IL-6 and its downstream signaling components on stem cell biology, particularly the chemoresistance of CSCs, to explore potential molecular targets for cancer therapy. The colon cancer cell line WiDr was cultured in serum-free, non-adherent, and three-dimensional spheroid-forming conditions to enrich the stem cell-like population. Spheroid-forming cells slowly proliferated and expressed high levels of Oct-4, Klf4, Bmi-1, Lgr5, IL-6, and Notch 3 compared with adherent cells. Treatment with an antihuman IL-6 receptor monoclonal antibody reduced spheroid formation, stem cell-related gene expression, and 5-fluorouracil (5-FU) resistance. In addition, IL-6 treatment enhanced the levels of p-STAT3 (Tyr705), the expression of Oct-4, Klf4, Lgr5, and Notch 3, and chemoresistance to 5-FU. siRNA targeting Notch 3 suppressed spheroid formation, Oct-4 and Lgr5 expression, and 5-FU chemoresistance, whereas STAT3 inhibition enhanced Oct-4, Klf4, Lgr5, and Notch 3 expression and 5-FU chemoresistance along with reduced spheroid growth. Taken together, these results indicate that IL-6 functions in dichotomous pathways involving Notch 3 induction and STAT3 activation. The former pathway is involved in cancer stem-like cell biology and enhanced chemoresistance, and the latter pathway leads to accelerated proliferation and reduced chemoresistance. Thus, an anti-human IL-6 receptor monoclonal antibody or Notch 3 inhibition may be superior to STAT3 inhibition for CSC-targeting therapies concomitant with anticancer drugs.

Original languageEnglish
Pages (from-to)1551-1559
Number of pages9
JournalInternational journal of oncology
Volume46
Issue number4
DOIs
Publication statusPublished - 2015 Apr 1

Keywords

  • Cancer stem cells
  • Colon cancer
  • IL-6
  • Notch 3
  • STAT3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Ying, J., Tsujii, M., Kondo, J., Hayashi, Y., Kato, M., Akasaka, T., Inoue, T., Shiraishi, E., Inoue, T., Hiyama, S., Tsujii, Y., Maekawa, A., Kawai, S., Fujinaga, T., Araki, M., Shinzaki, S., Watabe, K., Nishida, T., Iijima, H., & Takehara, T. (2015). The effectiveness of an anti-human IL-6 receptor monoclonal antibody combined with chemotherapy to target colon cancer stem-like cells. International journal of oncology, 46(4), 1551-1559. https://doi.org/10.3892/ijo.2015.2851