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SRC family kinase FYN promotes the neuroendocrine phenotype and visceral metastasis in advanced prostate cancer

Murali Gururajan, Karen A. Cavassani, Margarit Sievert, Peng Duan, Jake Lichterman, Jen-Ming Huang, Bethany Smith, Sungyong You, Srinivas Nandana, Gina Chia-Yi Chu, Sheldon Mink, Sajni Josson, Chunyan Liu, Matteo Morello, Lawrence W. M. Jones, Jayoung Kim, Michael R. Freeman, Neil Bhowmick, Haiyen E. Zhau, Leland W.K. Chung and Edwin M. Posadas _

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Oncotarget. 2015; 6:44072-44083. https://doi.org/10.18632/oncotarget.6398

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Abstract

Murali Gururajan1,*, Karen A. Cavassani1,*, Margarit Sievert1, Peng Duan1, Jake Lichterman1, Jen-Ming Huang1, Bethany Smith1, Sungyong You1,2, Srinivas Nandana1, Gina Chia-Yi Chu1, Sheldon Mink1, Sajni Josson1, Chunyan Liu1, Matteo Morello1,3, Lawrence W. M. Jones4, Jayoung Kim1,3, Michael R. Freeman1,3, Neil Bhowmick3, Haiyen E. Zhau1,2, Leland W.K. Chung1,2, Edwin M. Posadas1,2

1Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

2Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

3Cancer Biology Program, Departments of Surgery, Medicine, and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

4Urological Research, Huntington Medical Research Institutes, Pasadena, CA 91101, USA

*These authors contributed equally to this work

Correspondence to:

Edwin Posadas, e-mail: Edwin.Posadas@csmc.edu

Keywords: SRC kinase, NEPC, metastasis, neuroendocrine, prostate cancer

Received: September 06, 2015     Accepted: November 14, 2015     Published: November 26, 2015

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.


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