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 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.

• Authors: Yuma Wada, Kazunori Tokuda, Yuji Morine, Shohei Okikawa, Shoko Yamashita, Tetsuya Ikemoto, Satoru Imura, Yu Saito, Shinichiro Yamada, Mitsuo Shimada
• Journal: Oncotarget (Oncotarget) Vol. 11 Issue 49 Pg. 4593-4604 (Dec 08 2020) ISSN: 1949-2553 [Electronic] United States
• PMID: 33346211 (Publication Type: Journal Article)
• Copyright: Copyright: © 2020 Wada et al.