Transcription Factor Signal Transducer and Activator of Transcription 5 Promotes Growth of Human Prostate Cancer Cells In vivo

• Published in: Clinical cancer research Vol. 14; no. 5; pp. 1317 - 1324
• Main Authors: DAGVADORJ, Ayush, KIRKEN, Robert A, LEIBY, Benjamin, KARRAS, James, NEVALAINEN, Marja T
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2008
• Subjects: Adenoviridae - genetics; Animals; Antineoplastic agents; bcl-X Protein - metabolism; Biological and medical sciences; Blotting, Western; Cell Survival; Cyclin D; Cyclins - metabolism; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Genes, Dominant; Gynecology. Andrology. Obstetrics; Humans; in vivo; Male; Male genital diseases; Medical sciences; Mice; Mice, Nude; Nephrology. Urinary tract diseases; Oligonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; Promoter Regions, Genetic - genetics; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; RNA, Small Interfering - pharmacology; Signal Transduction; STAT5 Transcription Factor - antagonists & inhibitors; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Stat5a/b; Survival Rate; Transcription, Genetic; Tumor Cells, Cultured; tumor growth; Tumor Stem Cell Assay; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Xenograft Model Antitumor Assays; Human; Urinary system disease; Prostate disease; Transcription; Growth; Malignant tumor; In vivo; Signal transduction; Activator; Transcription factor; Male genital diseases; Prostate cancer; Tumor cell; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-2024

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.