Department of Obstetrics and Gynecology, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, Neihu, Taipei 11490, Taiwan.
Evid Based Complement Alternat Med. 2012;2012:350239. doi: 10.1155/2012/350239. Epub 2012 Dec 24.
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.
雷公藤红素（TPL）抑制多种癌细胞的增殖，被认为是一种有效的抗癌药物。在本研究中，我们证明 TPL 下调口腔、卵巢和乳腺癌细胞中的 HER2 蛋白表达。它以剂量和时间依赖的方式抑制 HER2 蛋白表达。TPL 对 HER2 启动子活性的转录抑制也被观察到。TPL 在 HER2 启动子区域的相互作用位点位于-207 至-103 bps 之间，其中包括转录因子 NF-κB 的一个假定结合位点。先前的报告表明 TPL 抑制 NF-κB 的表达。我们证明，NF-κB 的过表达分别挽救了 TPL 介导的 NIH3T3 细胞和卵巢癌细胞中 HER2 启动子活性和蛋白表达的抑制。此外，TPL 下调 HER2、磷酸肌醇 3-激酶（PI3K）和丝氨酸/苏氨酸特异性蛋白激酶（Akt）的激活（磷酸化）形式。TPL 还抑制了小鼠模型中的肿瘤生长。此外，TPL 基于免疫组织化学（IHC）检测抑制异种移植肿瘤中的 HER2 和 Ki-67 表达。这些发现表明 TPL 可以转录抑制 HER2 并抑制下游的 PI3K/Akt 信号通路。我们的研究表明 TPL 可以抑制肿瘤生长，因此可能成为一种有潜力的化疗药物。
