MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells.
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Date
2012Author
Rajabi, H
Ahmad, R
Jin, C
Joshi, MD
Guha, M
Alam, M
Kharbanda, S
Kufe, D
Type
ArticleLanguage
enMetadata
Show full item recordAbstract
BACKGROUND:
The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer.
METHODS:
Effects of MUC1-C on androgen receptor (AR) expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays, and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium, and sensitivity to MUC1-C inhibitors.
RESULTS:
The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain (DBD). In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice.
CONCLUSIONS:
These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition.
URI
http://www.ncbi.nlm.nih.gov/pubmed/22473899http://erepository.uonbi.ac.ke:8080/xmlui/handle/123456789/52656
Citation
Prostate. 2012 Nov;72(15):1659-68. doi: 10.1002/pros.22519. Epub 2012 Apr 2.Publisher
University of Nairobi Faculty of medicine
Collections
- Faculty of Health Sciences (FHS) [10387]