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


ABSTRACT:

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 ?g/ml). Activated HSCs (aHSCs) were detected by ?-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 ?-SMA and IL-6 mRNA expressions of aHSC. ?-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.

SUBMITTER: Wada Y 

PROVIDER: S-EPMC7733620 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Wada Yuma Y   Tokuda Kazunori K   Morine Yuji Y   Okikawa Shohei S   Yamashita Shoko S   Ikemoto Tetsuya T   Imura Satoru S   Saito Yu Y   Yamada Shinichiro S   Shimada Mitsuo M  

Oncotarget 20201208 49


<h4>Introduction</h4>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.<h4>Materials and methods</h4>The HSCs (LX2) were cultured in colon cancer cells (HCT116 and  ...[more]

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