Transcription factor signal transducer and activator of transcription 5 promotes growth of human prostate cancer cells in vivo. Clin Cancer Res 2008 Mar 01;14(5):1317-24
Date
03/05/2008Pubmed ID
18316550DOI
10.1158/1078-0432.CCR-07-2024Scopus ID
2-s2.0-40949103423 (requires institutional sign-in at Scopus site) 89 CitationsAbstract
PURPOSE: Signal transducer and activator of transcription 5a/b (Stat5a/b) is the key mediator of prolactin effects in prostate cancer cells via activation of Janus-activated kinase 2. Prolactin is a locally produced growth factor in human prostate cancer. Prolactin protein expression and constitutive activation of Stat5a/b are associated with high histologic grade of clinical prostate cancer. Moreover, activation of Stat5a/b in primary prostate cancer predicts early disease recurrence. Here, we inhibited Stat5a/b by several different methodologic approaches. Our goal was to establish a proof of principle that Stat5a/b is critical for prostate cancer cell viability in vitro and for prostate tumor growth in vivo.
EXPERIMENTAL DESIGN: We inhibited Stat5a/b protein expression by antisense oligonucleotides or RNA interference and transcriptional activity of Stat5a/b by adenoviral expression of a dominant-negative mutant of Stat5a/b in prostate cancer cells in culture. Moreover, Stat5a/b activity was suppressed in human prostate cancer xenograft tumors in nude mice. Stat5a/b regulation of Bcl-X(L) and cyclin D1 protein levels was shown by antisense suppression of Stat5a/b protein expression followed by Western blotting.
RESULTS AND CONCLUSIONS: We show here that inhibition of Stat5a/b by antisense oligonucleotides, RNA interference, or adenoviral expression of dominant-negative Stat5a/b effectively kills prostate cancer cells. Moreover, we show that Stat5a/b is critical for human prostate cancer xenograft growth in nude mice. The effects of Stat5a/b on the viability of prostate cancer cells involve Stat5a/b regulation of Bcl-X(L) and cyclin D1 protein levels but not the expression or activation of Stat3. This work establishes Stat5a/b as a therapeutic target protein for prostate cancer. Pharmacologic inhibition of Stat5a/b in prostate cancer can be achieved by small-molecule inhibitors of transactivation, dimerization, or DNA binding of Stat5a/b.
Author List
Dagvadorj A, Kirken RA, Leiby B, Karras J, Nevalainen MTMESH terms used to index this publication - Major topics in bold
AdenoviridaeAnimals
Blotting, Western
Cell Survival
Cyclin D
Cyclins
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation, Neoplastic
Genes, Dominant
Humans
Male
Mice
Mice, Nude
Oligonucleotides, Antisense
Promoter Regions, Genetic
Prostatic Neoplasms
RNA, Small Interfering
STAT5 Transcription Factor
Signal Transduction
Survival Rate
Transcription, Genetic
Tumor Cells, Cultured
Tumor Stem Cell Assay
Xenograft Model Antitumor Assays
bcl-X Protein