title: Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells.
abstract: Signal transducers and activators of transcription (STATs) were identified originally as key components of cytokine signaling pathways. More recently, constitutive activation of STAT proteins has been detected in a wide variety of human tumor specimens and tumor cell lines. Here, we examined the activation of one STAT family member, Stat3, in human prostate cancer cell lines and primary prostate tumors. An analysis of 45 adenocarcinomas obtained at radical prostatectomy revealed elevated levels of constitutive Stat3 activation in 37 (82%) of 45 of the tumors compared with matched adjacent nontumor prostate tissues. A highly specific immunohistochemical assay for detection of phospho-Stat3 revealed that elevated Stat3 activity was localized primarily in the tumor cells of prostate carcinoma specimens. Furthermore, higher levels of Stat3 activation in patient specimens were correlated significantly with more malignant tumors exhibiting higher Gleason scores. In addition, all of the three human prostate cancer cell lines examined (DU145, PC3, and LNCaP) displayed constitutive activation of Stat3. Substantially lower levels of Stat3 activation were detected in LNCaP cells; however, stimulation with interleukin 6 induced a significant increase in Stat3 DNA-binding activity in these cells. Moreover, the direct inhibition of constitutive Stat3 signaling in DU145 cells using antisense Stat3 oligonucleotides induced growth inhibition and apoptosis. Our findings demonstrate that constitutive activation of Stat3 occurs frequently in primary prostate adenocarcinomas and is critical for the growth and survival of prostate cancer cells. These studies further suggest that Stat3 signaling represents a potentially novel molecular target for prostate cancer therapy.
authors.affiliation: Department of Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
authors.forename: Linda B
authors.initials: LB
authors.lastname: Mora
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.forename: John
authors.initials: J
authors.lastname: Seigne
authors.forename: Jose
authors.initials: J
authors.lastname: Diaz
authors.forename: Nazeel
authors.initials: N
authors.lastname: Ahmad
authors.forename: Roy
authors.initials: R
authors.lastname: Garcia
authors.forename: Tammy
authors.initials: T
authors.lastname: Bowman
authors.forename: Robert
authors.initials: R
authors.lastname: Falcone
authors.forename: Rita
authors.initials: R
authors.lastname: Fairclough
authors.forename: Alan
authors.initials: A
authors.lastname: Cantor
authors.forename: Carlos
authors.initials: C
authors.lastname: Muro-Cacho
authors.forename: Sandy
authors.initials: S
authors.lastname: Livingston
authors.forename: James
authors.initials: J
authors.lastname: Karras
authors.forename: Julio
authors.initials: J
authors.lastname: Pow-Sang
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators