title: Autocrine prolactin promotes prostate cancer cell growth via Janus kinase-2-signal transducer and activator of transcription-5a/b signaling pathway.
abstract: The molecular mechanisms that promote progression of localized prostate cancer to hormone-refractory and disseminated disease are poorly understood. Prolactin (Prl) is a local growth factor produced in high-grade prostate cancer, and exogenously added Prl in tissue or explant cultures of normal and malignant prostate is a strong mitogen and survival factor for prostate epithelium. The key signaling proteins that mediate the biological effects of Prl in prostate cancer are Signal Transducer and Activator of Transcription (Stat)-5a/5b via activation of Janus kinase-2. Importantly, inhibition of Stat5a/b in prostate cancer cells induces apoptotic death. Using a specific Prl receptor antagonist (Delta1-9G129R-hPRL), we demonstrate here for the first time that autocrine Prl in androgen-independent human prostate cancer cells promotes cell viability via Stat5 signaling pathway. Furthermore, we examined a unique clinical material of human hormone refractory prostate cancers and metastases and show that autocrine Prl is expressed in 54% of hormone-refractory clinical human prostate cancers and 62% prostate cancer metastases. Finally, we demonstrate that autocrine Prl is expressed from both the proximal and distal promoters of the Prl gene in clinical human prostate cancers and in vivo and in vitro human prostate cancer models, independently of pituitary transcription factor-1 (Pit-1). Collectively, the data provide novel evidence for the concept that autocrine Prl signaling pathway is involved in growth of hormone-refractory and metastatic prostate cancer. The study also provides support for the use of Prl receptor antagonists or other therapeutic strategies to block the Prl-Janus kinase-2-Stat5 signaling pathway in advanced prostate cancer.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, BLSB 309B, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA, and Department of Surgery, University Hospital of Turku, Finland.
authors.forename: Ayush
authors.initials: A
authors.lastname: Dagvadorj
authors.forename: Sean
authors.initials: S
authors.lastname: Collins
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Jomain
authors.forename: Junaid
authors.initials: J
authors.lastname: Abdulghani
authors.forename: James
authors.initials: J
authors.lastname: Karras
authors.forename: Tobias
authors.initials: T
authors.lastname: Zellweger
authors.forename: Hongzhen
authors.initials: H
authors.lastname: Li
authors.forename: Martti
authors.initials: M
authors.lastname: Nurmi
authors.forename: Kalle
authors.initials: K
authors.lastname: Alanen
authors.forename: Tuomas
authors.initials: T
authors.lastname: Mirtti
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.forename: Marja T
authors.initials: MT
authors.lastname: Nevalainen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D020319:Oligodeoxyribonucleotides, Antisense; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011388:Prolactin; D053614:Janus Kinase 2