title: The Fer tyrosine kinase acts as a downstream interleukin-6 effector of androgen receptor activation in prostate cancer.
abstract: Castrate-resistant prostate cancer (CRPC) is invariably lethal and still poorly understood. IL-6/pSTAT3 appears critical as elevated IL-6 and pSTAT3 correlate with CRPC and poor prognosis. We previously reported on the Fer tyrosine kinase being an integral component of the IL-6 pathway in PC by controlling STAT3. Since IL-6 also controls androgen receptor (AR) signaling via pSTAT3, we tested if Fer participates in this cross-talk. We report for the first time that in addition to STAT3, Fer is required for IL-6 mediated AR activation by phosphorylating AR tyrosine 223 and binding via its SH2 domain. Fer controls IL-6 induced growth response and PSA expression, while modestly contributing to EGF and IGF-1 effects. Finally, Fer, AR and pSTAT3 co-localize in the PC cell nucleus, including in prostate tissues from CRPC patients. Altogether these findings support a Fer contribution to aberrant AR signaling via pSTAT3 cross-talks during CRPC progression.
authors.affiliation: Urologic Oncology Research Group, Departments of Surgery (Urology Division), Medicine, and Oncology, McGill University Health Center (MUHC) Research Institute (RI), Canada.
authors.forename: Joice
authors.initials: J
authors.lastname: Rocha
authors.forename: Fatima Z
authors.initials: FZ
authors.lastname: Zouanat
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.forename: Lucie
authors.initials: L
authors.lastname: Hamel
authors.forename: Tarik
authors.initials: T
authors.lastname: Benidir
authors.forename: Eleonora
authors.initials: E
authors.lastname: Scarlata
authors.forename: Fadi
authors.initials: F
authors.lastname: Brimo
authors.forename: Armen
authors.initials: A
authors.lastname: Aprikian
authors.forename: Simone
authors.initials: S
authors.lastname: Chevalier
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology*; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000502:physiology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C052602:proto-oncogene protein c-fes-fps; D011505:Protein-Tyrosine Kinases; D017430:Prostate-Specific Antigen
keywords: Androgen independence; Androgen receptor; Castration resistance; Fer tyrosine kinase; IL-6/STAT3; Tyrosine phosphorylation