Abstract 2954: Novel interaction between FLIP/DAPK: role for RON in androgen-independent prostate cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.2954-2954
• Main Authors: Batth, Izhar S., Gong, Jingjing, Kumar, A. Pratap
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-2954

Patients with Hormone refractory metastatic prostate cancer (HRPCA) have a 5-year survival of less than 30%. Therefore, it is imperative that new therapeutic strategies targeting advanced stage prostate cancer (PCA) be developed. 2-Methoxyestradio (2-ME2) is an endogenously produced compound that has been shown to successfully treat PCA. As part of our efforts in understanding its mechanism of action, we discovered that the tyrosine kinase RON (Recepteur ‘Origine Nantais) was a target for inhibition. RON Kinase has been previously shown to be upregulated in murine PCA. RON has also been reported to mediate cell migration, and invasion in various cancers. However, the precise role of RON signaling in prostate carcinogenesis is unclear. Our data revealed that RON is upregulated in HRPCA cell lines and human prostate tumors. Using genetic approaches we found novel, causal association between RON and FLICE-like inhibitory protein, also known as FLIP (a known target of 2-ME2), and an increase in Death Associated Protein Kinase (DAPK1). Interestingly, RON overexpression in early stage PCA cell lines induced the transcriptional activation of the Androgen Receptor (AR) and FLIP. Stimulation of RON with its ligand MSP (macrophage stimulating protein) also yielded heightened promoter activity of AR and its downstream target genes including PSA and FLIP. Functionally, these responses translated to increased cell migration in RON overexpressing cells and loss of this migratory potential with RON silencing. Interestingly, 2-ME2 treatment also reduced the migration of HRPCA cells. Migration in wild-type HRPCA cells is also sensitive to regulation with 2-ME2 treatment. Overall these data suggests that RON kinase is a major player in promoting advanced-stage prostate cancer in part due to its ability to regulate apoptosis through novel FLIP/DAPK1 interaction. Supported by NIH (CA 135451, APK). Citation Format: Izhar S. Batth, Jingjing Gong, A. Pratap Kumar. Novel interaction between FLIP/DAPK: role for RON in androgen-independent prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2954. doi:10.1158/1538-7445.AM2013-2954