Triptolide inhibits the proliferation of prostate cancer cells and down-regulates SUMO-specific protease 1 expression.
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.
Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University, Yangling, Shaanxi Province, People's Republic of China.
Weiwei
W
Huang
Tiantian
T
He
Chengsen
C
Chai
Yuan
Y
Yang
Yahong
Y
Zheng
Pei
P
Zhou
Xiaoxia
X
Qiao
Bin
B
Zhang
Zengzhen
Z
Liu
Junru
J
Wang
Changhong
C
Shi
Liping
L
Lei
Kun
K
Gao
Hewei
H
Li
Sue
S
Zhong
Libo
L
Yao
Meng-Er
ME
Huang
Ming
M
Lei
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003546:Cysteine Endopeptidases; D018450:Disease Progression; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D004852:Epoxy Compounds / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D008297:Male; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D012333:RNA, Messenger; D011944:Receptors, Androgen; C001899:triptolide; D048031:JNK Mitogen-Activated Protein Kinases; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases