Autocrine prolactin promotes prostate cancer cell growth via Janus kinase-2-signal transducer and activator of transcription-5a/b signaling pathway. Endocrinology 2007 Jul;148(7):3089-101
Date
04/07/2007Pubmed ID
17412813DOI
10.1210/en.2006-1761Scopus ID
2-s2.0-34347271908 (requires institutional sign-in at Scopus site) 116 CitationsAbstract
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.
Author List
Dagvadorj A, Collins S, Jomain JB, Abdulghani J, Karras J, Zellweger T, Li H, Nurmi M, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Goffin V, Nevalainen MTMESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Cell Survival
Gene Expression Regulation, Neoplastic
Humans
Immunoblotting
Janus Kinase 2
Male
Mice
Mice, Nude
Neoplasm Metastasis
Neoplasms, Experimental
Oligodeoxyribonucleotides, Antisense
Phosphorylation
Prolactin
Promoter Regions, Genetic
Prostatic Neoplasms
Reverse Transcriptase Polymerase Chain Reaction
STAT5 Transcription Factor
Signal Transduction
Transcription, Genetic
Transplantation, Heterologous
Tumor Suppressor Proteins
Tyrphostins
