Triptolide Transcriptionally Represses HER2 in Ovarian Cancer Cells by Targeting NF-κB.
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.
Department of Obstetrics and Gynecology, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, Neihu, Taipei 11490, Taiwan.
Chien-Chih
CC
Ou
Yuan-Wu
YW
Chen
Shih-Chung
SC
Hsu
Huey-Kang
HK
Sytwu
Shih-Hurng
SH
Loh
Jhy-Wei
JW
Li
Jah-Yao
JY
Liu