Research Papers:

The inhibitory effect of TU-100 on hepatic stellate cell activation in the tumor microenvironment

Yuma Wada, Kazunori Tokuda, Yuji Morine _, Shohei Okikawa, Shoko Yamashita, Tetsuya Ikemoto, Satoru Imura, Yu Saito, Shinichiro Yamada and Mitsuo Shimada

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Oncotarget. 2020; 11:4593-4604. https://doi.org/10.18632/oncotarget.27835

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Yuma Wada1,*, Kazunori Tokuda1,*, Yuji Morine1, Shohei Okikawa1, Shoko Yamashita1, Tetsuya Ikemoto1, Satoru Imura1, Yu Saito1, Shinichiro Yamada1 and Mitsuo Shimada1

1 Department of Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

* These authors contributed equally to this work

Correspondence to:

Yuji Morine,email: [email protected]

Keywords: CRLM; TU-100; HSC; CRC; IL-6

Received: May 19, 2020     Accepted: November 19, 2020     Published: December 08, 2020

Copyright: © 2020 Wada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction: The tumor microenvironment is involved in acquiring tumor malignancies of colorectal liver metastasis (CRLM). We have reported that TU-100 (Daikenchuto) suppresses hepatic stellate cell (HSC) activation in obstructive jaundice. In this study, we report new findings as the direct and indirect inhibitory effects of TU-100 on cancer cell growth through the suppression of HSC activation.

Materials and Methods: The HSCs (LX2) were cultured in colon cancer cells (HCT116 and HT29)-conditioned medium (CM) with or without TU-100 treatment (90, 270, 900 μg/ml). Activated HSCs (aHSCs) were detected by α-SMA and IL-6 mRNA expressions and cytokine arrays of HSC’s culture supernatants. Cancer cell growth was analyzed for proliferation and migration ability, compared with TU-100 treatment. To investigate the direct anti-tumor effect of TU-100, cancer cells were cultured in the presence of aHSC-CM and TU-100 (90, 270, 900) or aHSC-CM alone, and assessed autophagosomes, conversion to LC3-II protein, and Beclin-1 mRNA expression.

Results: Colon cancer-CM significantly increased α-SMA and IL-6 mRNA expressions of aHSC. α-SMA and IL-6 mRNA expressions of aHSC, and IL-6 secretions from aHSCs were significantly decreased with TU-100 (270, 900) treatment, compared to colon cancer-CM alone. Compared with normal culture medium, aHSC-CM led to a significantly increased cell number and modified HSC-CM (TU-100; 270, 900) significantly suppressed cancer cell growth and migration. TU-100 (900) treatment induced autophagy and significantly promoted the autophagic cell death.

Conclusions: TU-100 inhibited colon cancer cell malignant potential by both suppressing HSC activation and inducing directly autophagy of cancer cells.

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