title: Celastrol suppresses tumor cell growth through targeting an AR-ERG-NF-κB pathway in TMPRSS2/ERG fusion gene expressing prostate cancer.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, Texas, USA.
authors.forename: Longjiang
authors.initials: L
authors.lastname: Shao
authors.forename: Zhansong
authors.initials: Z
authors.lastname: Zhou
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.forename: Patricia
authors.initials: P
authors.lastname: Castro
authors.forename: Olga
authors.initials: O
authors.lastname: Dakhov
authors.forename: Ping
authors.initials: P
authors.lastname: Shi
authors.forename: Yaoxia
authors.initials: Y
authors.lastname: Bai
authors.forename: Huixiang
authors.initials: H
authors.lastname: Ji
authors.forename: Wenhao
authors.initials: W
authors.lastname: Shen
authors.forename: Jianghua
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis*; D053978:Pentacyclic Triterpenes; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D053978:Pentacyclic Triterpenes; C498143:RELA protein, human; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000071230:Transcriptional Regulator ERG; D014315:Triterpenes; C050414:celastrol
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