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

// Murali Gururajan 1, * , Karen A. Cavassani 1, * , Margarit Sievert 1 , Peng Duan 1 , Jake Lichterman 1 , Jen-Ming Huang 1 , Bethany Smith 1 , Sungyong You 1, 2 , Srinivas Nandana 1 , Gina Chia-Yi Chu 1 , Sheldon Mink 1 , Sajni Josson 1 , Chunyan Liu 1 , Matteo Morello 1, 3 , Lawrence W. M. Jones 4 , Jayoung Kim 1, 3 , Michael R. Freeman 1, 3 , Neil Bhowmick 3 , Haiyen E. Zhau 1, 2 , Leland W.K. Chung 1, 2 , Edwin M. Posadas 1, 2 1 Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 2 Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 3 Cancer Biology Program, Departments of Surgery, Medicine, and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 4 Urological 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 ARCaP M 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.