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

PLoS One. 2013;8(3):e58391. doi: 10.1371/journal.pone.0058391. Epub 2013 Mar 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Oncogene Proteins, Fusion / biosynthesis*
  • Pentacyclic Triterpenes
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology
  • Receptors, Androgen / metabolism*
  • Signal Transduction / drug effects*
  • Trans-Activators / metabolism*
  • Transcription Factor RelA / metabolism*
  • Transcriptional Regulator ERG
  • Triterpenes / pharmacology*


  • AR protein, human
  • Antineoplastic Agents
  • ERG protein, human
  • Oncogene Proteins, Fusion
  • Pentacyclic Triterpenes
  • RELA protein, human
  • Receptors, Androgen
  • TMPRSS2-ERG fusion protein, human
  • Trans-Activators
  • Transcription Factor RelA
  • Transcriptional Regulator ERG
  • Triterpenes
  • celastrol