title: SRC family kinase FYN promotes the neuroendocrine phenotype and visceral metastasis in advanced prostate cancer.
abstract: FYN is a SRC family kinase (SFK) that has been shown to be up-regulated in human prostate cancer (PCa) tissues and cell lines. In this study, we observed that FYN is strongly up-regulated in human neuroendocrine PCa (NEPC) tissues and xenografts, as well as cells derived from a NEPC transgenic mouse model. In silico analysis of FYN expression in prostate cancer cell line databases revealed an association with the expression of neuroendocrine (NE) markers such as CHGA, CD44, CD56, and SYP. The loss of FYN abrogated the invasion of PC3 and ARCaPM cells in response to MET receptor ligand HGF. FYN also contributed to the metastatic potential of NEPC cells in two mouse models of visceral metastasis with two different cell lines (PC3 and TRAMPC2-RANKL). The activation of MET appeared to regulate neuroendocrine (NE) features as evidenced by increased expression of NE markers in PC3 cells with HGF. Importantly, the overexpression of FYN protein in DU145 cells was directly correlated with the increase of CHGA. Thus, our data demonstrated that the neuroendocrine differentiation that occurs in PCa cells is, at least in part, regulated by FYN kinase. Understanding the role of FYN in the regulation of NE markers will provide further support for ongoing clinical trials of SFK and MET inhibitors in castration-resistant PCa patients.
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Gururajan
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Cavassani
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Margarit
authors.initials: M
authors.lastname: Sievert
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Duan
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Lichterman
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jen-Ming
authors.initials: JM
authors.lastname: Huang
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Smith
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Sungyong
authors.initials: S
authors.lastname: You
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Nandana
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Gina Chia-Yi
authors.initials: GC
authors.lastname: Chu
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Mink
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Sajni
authors.initials: S
authors.lastname: Josson
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Cancer Biology Program, Departments of Surgery, Medicine, and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Morello
authors.affiliation: Urological Research, Huntington Medical Research Institutes, Pasadena, CA 91101, USA.
authors.forename: Lawrence W M
authors.initials: LW
authors.lastname: Jones
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Cancer Biology Program, Departments of Surgery, Medicine, and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Cancer Biology Program, Departments of Surgery, Medicine, and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
authors.affiliation: Cancer Biology Program, Departments of Surgery, Medicine, and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Bhowmick
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.affiliation: Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Posadas
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D053379:Chromogranin A / Q000378:metabolism; D003198:Computer Simulation; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D008297:Male; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D018358:Neuroendocrine Tumors / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C506150:CHGA protein, human; D053379:Chromogranin A; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn
keywords: NEPC; SRC kinase; metastasis; neuroendocrine; prostate cancer