Triptolide Transcriptionally Represses HER2 in Ovarian Cancer Cells by Targeting NF-κB

Chien-Chih Ou,Shih-Chung Hsu,Jhy-Wei Li,Huey-Kang Sytwu,Yuan-Wu Chen,Shih-Hurng Loh,Jah-Yao Liu

doi:10.1155/2012/350239

Abstract

Triptolide (TPL) inhibits the proliferation of a variety of cancer cells and has been proposed as an effective anticancer agent. In this study, we demonstrate that TPL downregulates HER2 protein expression in oral, ovarian, and breast cancer cells. It suppresses HER2 protein expression in a dose- and time-dependent manner. Transrepression of HER2 promoter activity by TPL is also observed. The interacting site of TPL on the HER2 promoter region is located between −207 and −103 bps, which includes a putative binding site for the transcription factor NF-κB. Previous reports demonstrated that TPL suppresses NF-κB expression. We demonstrate that overexpression of NF-κB rescues TPL-mediated suppression of HER2 promoter activity and protein expression in NIH3T3 cells and ovarian cancer cells, respectively. In addition, TPL downregulates the activated (phosphorylated) forms of HER2, phosphoinositide-3 kinase (PI3K), and serine/threonine-specific protein kinase (Akt). TPL also inhibits tumor growth in a mouse model. Furthermore, TPL suppresses HER2 and Ki-67 expression in xenografted tumors based on an immunohistochemistry (IHC) assay. These findings suggest that TPL transrepresses HER2 and suppresses the downstream PI3K/Akt-signaling pathway. Our study reveals that TPL can inhibit tumor growth and thereby may serve as a potential chemotherapeutic agent.

Highlights

Triptolide (TPL) is a diterpenoid triepoxide derived from the herb Tripterygium wilfordii [1]
We demonstrate that overexpression of nuclear factor-κB (NF-κB) rescues TPL-mediated suppression of HER2 promoter activity and protein expression in NIH3T3 cells and ovarian cancer cells, respectively
TPL, a pure compound extracted from the traditional Chinese medicinal plant T. wilfordii, has significant cytotoxic effects on different types of tumors

Summary

Introduction

Triptolide (TPL) is a diterpenoid triepoxide derived from the herb Tripterygium wilfordii [1]. It was found that TPL reduces proliferation and induces apoptosis in cancer cells [2,3,4]. It inhibits tumor growth and metastases in mouse xenografts of melanoma, breast cancer, gastric carcinoma, bladder cancer [3], and pancreatic cancer [4]. We found that TPL has a strong antitumor effect against oral cancer cells through caspase-mediated apoptosis [5]. TPL circumvents drug resistance and enhances the antitumor effect of 5-fluorouracil [6]. The understanding of the molecular mechanisms by which TPL inhibits cancer cell growth may shed light on cancer therapy

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Results

Conclusion