2-(4-Hydroxy-3-methoxyphenyl)-benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase CHIP.

Hiromi Hiyoshi,Yasunari Kanda,Mai Tsuchiya,Kazuo Nagasawa,Naoya Hirata,Yuka Nakajima,Junn Yanagisawa,Keisuke Iida,Natsuka Goto

doi:10.1038/srep07095

Abstract

Breast cancer is the most common malignancy among women and has poor survival and high recurrence rates for aggressive metastatic disease. Notably, triple-negative breast cancer (TNBC) is a highly aggressive cancer and there is no preferred agent for TNBC therapy. In this study, we show that a novel agent, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109), has ability to inhibit breast cancer cell growth and invasiveness in vitro and in vivo. In addition, YL-109 repressed the sphere-forming ability and the expression of stem cell markers in MDA-MB-231 mammosphere cultures. YL-109 increased the expression of carboxyl terminus of Hsp70-interacting protein (CHIP), which suppresses tumorigenic and metastatic potential of breast cancer cells by inhibiting the oncogenic pathway. YL-109 induced CHIP transcription because of the recruitment of the aryl hydrocarbon receptor (AhR) to upstream of CHIP gene in MDA-MB-231 cells. Consistently, the antitumor effects of YL-109 were depressed by CHIP or AhR knockdown in MDA-MB-231 cells. Taken together, our findings indicate that a novel agent YL-109 inhibits cell growth and metastatic potential by inducing CHIP expression through AhR signaling and reduces cancer stem cell properties in MDA-MB-231 cells. It suggests that YL-109 is a potential candidate for breast cancer therapy.

Highlights

Benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase carboxyl terminus of Hsp70-interacting protein (CHIP)
We previously reported that CHIP levels were much higher in MCF-7 cells, a non-aggressive cell line derived from human breast cancer cells, than in MDA-MB-231 cells, a highly aggressive cell line
In the present study, we revealed that the novel agent YL-109 has antitumor activity in triple-negative breast cancer (TNBC) cells

Summary

Introduction

Benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase CHIP. Our findings indicate that a novel agent YL-109 inhibits cell growth and metastatic potential by inducing CHIP expression through AhR signaling and reduces cancer stem cell properties in MDA-MB-231 cells. It suggests that YL-109 is a potential candidate for breast cancer therapy. CHIP is a U-box-type ubiquitin E3 ligase that induces ubiquitylation and degradation of its substrates These include several oncogenic proteins that suppress the tumorigenic and metastatic potential of breast cancer cells[6,7,8]. We hypothesized that ideal agents might exert the antitumor effects mediated by AhR signaling in both ER-positive and -negative breast cancer cells

Methods

Results

Conclusion