Celastrol suppresses tumor cell growth through targeting an AR-ERG-NF-κB pathway in TMPRSS2/ERG fusion gene expressing prostate cancer

The TMPRSS2/ERG (T/E) fusion gene is present in the majority of all prostate cancers (PCa). We have shown previously that NF-kB signaling is highly activated in these T/E fusion expressing cells via phosphorylation of NF-kB p65 Ser536 (p536). We therefore hypothesize that targeting NF-kB signaling m...

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Bibliographic Details
Published in:PloS one 2013-03, Vol.8 (3), p.e58391
Main Authors: Shao, Longjiang, Zhou, Zhansong, Cai, Yi, Castro, Patricia, Dakhov, Olga, Shi, Ping, Bai, Yaoxia, Ji, Huixiang, Shen, Wenhao, Wang, Jianghua
Format: Article
Language:English
Subjects:
Androgens
Angiogenesis
Animals
Antineoplastic Agents - pharmacology
Apoptosis
Biocompatibility
Biology
Cell fusion
Cell growth
Cell Line, Tumor
Chinese medicine
Cytokines
Dose-Response Relationship, Drug
Fusion protein
Gene Expression Regulation, Neoplastic - drug effects
Hospitals
Humans
Immunology
In vivo methods and tests
Inhibition
Kinases
Male
Medicine
Mice
Mice, Nude
NF-κB protein
Oncogene Proteins, Fusion - biosynthesis
Pathology
Phosphorylation
Prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Receptors, Androgen - metabolism
Signal transduction
Signal Transduction - drug effects
Signaling
Toxicity
Trans-Activators - metabolism
Transcription Factor RelA - metabolism
Transcriptional Regulator ERG
Triterpenes - pharmacology
Tumors
Urology
Veterans
Xenografts
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Summary:The TMPRSS2/ERG (T/E) fusion gene is present in the majority of all prostate cancers (PCa). We have shown previously that NF-kB signaling is highly activated in these T/E fusion expressing cells via phosphorylation of NF-kB p65 Ser536 (p536). We therefore hypothesize that targeting NF-kB signaling may be an efficacious approach for the subgroup of PCas that carry T/E fusions. Celastrol is a well known NF-kB inhibitor, and thus may inhibit T/E fusion expressing PCa cell growth. We therefore evaluated Celastrol's effects in vitro and in vivo in VCaP cells, which express the T/E fusion gene. VCaP cells were treated with different concentrations of Celastrol and growth inhibition and target expression were evaluated. To test its ability to inhibit growth in vivo, 0.5 mg/kg Celastrol was used to treat mice bearing subcutaneous VCaP xenograft tumors. Our results show Celastrol can significantly inhibit the growth of T/E fusion expressing PCa cells both in vitro and in vivo through targeting three critical signaling pathways: AR, ERG and NF-kB in these cells. When mice received 0.5 mg/kg Celastrol for 4 times/week, significant growth inhibition was seen with no obvious toxicity or significant weight loss. Therefore, Celastrol is a promising candidate drug for T/E fusion expressing PCa. Our findings provide a novel strategy for the targeted therapy which may benefit the more than half of PCa patients who have T/E fusion expressing PCas.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0058391