title: SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer.
abstract: Anabolic signals such as androgens and the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis play an essential role in the normal development of the prostate but also in its malignant transformation. In this study, we investigated the role of suppressor of cytokine signaling 2 (SOCS2) as mediator of the cross talk between androgens and GH signals in the prostate and its potential role as tumor suppressor in prostate cancer (PCa). We observed that SOCS2 protein levels assayed by immunohistochemistry are elevated in hormone therapy-naive localized prostatic adenocarcinoma in comparison with benign tissue. In contrast, however, castration-resistant bone metastases exhibit reduced levels of SOCS2 in comparison with localized or hormone naive, untreated metastatic tumors. In PCa cells, SOCS2 expression is induced by androgens through a mechanism that requires signal transducer and activator of transcription 5 protein (STAT5) and androgen receptor-dependent transcription. Consequentially, SOCS2 inhibits GH activation of Janus kinase 2, Src and STAT5 as well as both cell invasion and cell proliferation in vitro. In vivo, SOCS2 limits proliferation and production of IGF-1 in the prostate in response to GH. Our results suggest that the use of GH-signaling inhibitors could be of value as a complementary treatment for castration-resistant PCa.
  
  
  CONCLUSIONS
  Androgen induced SOCS2 ubiquitin ligase expression and inhibited GH signaling as well as cell proliferation and invasion in PCa, whereas reduced SOCS2 was present in castration-resistant cases. GH-signaling inhibitors might be a complementary therapeutic option for advanced PCa.
authors.affiliation: Molecular Endocrinology Group, Department of Disease Biology, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Diego
authors.initials: D
authors.lastname: Iglesias-Gato
authors.forename: Yin-Choy
authors.initials: YC
authors.lastname: Chuan
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wikström
authors.forename: Sandra
authors.initials: S
authors.lastname: Augsten
authors.forename: Ning
authors.initials: N
authors.lastname: Jiang
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Niu
authors.forename: Amanda
authors.initials: A
authors.lastname: Seipel
authors.forename: Daniela
authors.initials: D
authors.lastname: Danneman
authors.forename: Marcel
authors.initials: M
authors.lastname: Vermeij
authors.forename: Leandro
authors.initials: L
authors.lastname: Fernandez-Perez
authors.forename: Guido
authors.initials: G
authors.lastname: Jenster
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norstedt
authors.forename: Amilcar
authors.initials: A
authors.lastname: Flores-Morales
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019382:Human Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; C106643:SOCS2 protein, human; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D019382:Human Growth Hormone; D015741:Metribolone; D007334:Insulin-Like Growth Factor I