Journal Article

Triptolide Inhibits the Proliferation of Prostate Cancer Cells and Down-Regulates SUMO-Specific Protease 1 Expression

Shi, Changhong, Qiao, Xiaoxia, Zheng, Yahong, Lei, Liping, Yang, Yuan, Liu, Zengzhen, Yao, Libo, Wang, Junru, Huang, Meng-Er, Lei, Ming, He, Tiantian, Gao, Kun, Li, Hewei, Zhou, Pei, Zhong, Sue, Zhang, Bin, Huang, Weiwei, Chai, Chengsen

2012

Overview

Recently, traditional Chinese medicine and medicinal herbs have attracted more attentions worldwide for its anti-tumor efficacy. Celastrol and Triptolide, two active components extracted from the Chinese herb Tripterygium wilfordii Hook F (known as Lei Gong Teng or Thunder of God Vine), have shown anti-tumor effects. Celastrol was identified as a natural 26 s proteasome inhibitor which promotes cell apoptosis and inhibits tumor growth. The effect and mechanism of Triptolide on prostate cancer (PCa) is not well studied. Here we demonstrated that Triptolide, more potent than Celastrol, inhibited cell growth and induced cell death in LNCaP and PC-3 cell lines. Triptolide also significantly inhibited the xenografted PC-3 tumor growth in nude mice. Moreover, Triptolide induced PCa cell apoptosis through caspases activation and PARP cleavage. Unbalance between SUMOylation and deSUMOylation was reported to play an important role in PCa progression. SUMO-specific protease 1 (SENP1) was thought to be a potential marker and therapeutical target of PCa. Importantly, we observed that Triptolide down-regulated SENP1 expression in both mRNA and protein levels in dose-dependent and time-dependent manners, resulting in an enhanced cellular SUMOylation in PCa cells. Meanwhile, Triptolide decreased AR and c-Jun expression at similar manners, and suppressed AR and c-Jun transcription activity. Furthermore, knockdown or ectopic SENP1, c-Jun and AR expression in PCa cells inhibited the Triptolide anti-PCa effects. Taken together, our data suggest that Triptolide is a natural compound with potential therapeutic value for PCa. Its anti-tumor activity may be attributed to mechanisms involving down-regulation of SENP1 that restores SUMOylation and deSUMOyaltion balance and negative regulation of AR and c-Jun expression that inhibits the AR and c-Jun mediated transcription in PCa.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Androgens / Animals / Anticancer properties / Antineoplastic Agents - pharmacology / Antitumor agents / Apoptosis / Biology / Breast cancer / c-Jun protein / Cancer / Cancer treatment / Cell activation / Cell cycle / Cell death / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Chemical compounds / Chinese medicine / Cysteine Endopeptidases / Disease Progression / Diterpenes - pharmacology / Down-Regulation - drug effects / Endopeptidases - genetics / Endopeptidases - metabolism / Enzymes / Epoxy Compounds - pharmacology / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Herbal medicine / Herbs / Humans / JNK Mitogen-Activated Protein Kinases - genetics / Laboratories / Life sciences / Lymphatic system / Lymphoma / Male / Medicinal herbs / Medicinal plants / Medicine / Metastasis / Mice / Molecular biology / Mouse devices / Natural products / Pancreatic cancer / Pharmacology / Phenanthrenes - pharmacology / Poly(ADP-ribose) polymerase / Prostate cancer / Prostatic Neoplasms - pathology / Protease / Proteases / Proteasomes / Proteins / Receptors, Androgen - genetics / RNA polymerase / RNA, Messenger - genetics / RNA, Messenger - metabolism / Sumo / SUMO protein / Traditional Chinese medicine / Transcription factors / Transcription, Genetic - drug effects / Triptolide / Tumors / Xenograft Model Antitumor Assays / Xenografts