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

• Wada, Yuma

• Tokuda, Kazunori

• Morine, Yuji

• Okikawa, Shohei

• Yamashita, Shoko

• Ikemoto, Tetsuya

• Imura, Satoru

• Saito, Yu

• Yamada, Shinichiro

• Shimada, Mitsuo

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.

Journal

• Oncotarget

  Oncotarget 11 (49), 4593-4604, 2020-12-08

  Impact Journals

Keywords

• CRLM
• TU-100
• HSC
• CRC
• IL-6

Details

• CRID: 1050853987006421888
• NII Article ID: 120007188428
• ISSN: 19492553
• DOI: 10.18632/oncotarget.27835
• Web Site: http://repo.lib.tokushima-u.ac.jp/116616
• Web Site: https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.27835
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN