Abstract
BackgroundFGF receptor substrates (FRS2 and FRS3) are key adaptor proteins that mediate FGF-FGFR signalling in benign as well as malignant tissue. Here we investigated FRS2 and FRS3 as a means of disrupting global FGF signalling in prostate cancer.MethodsFRS2 and FRS3 manipulation was investigated in vitro using over-expression, knockdown and functional assays. FRS2 and FRS3 expression was profiled in cell lines and clinical tumors of different grades.ResultsIn a panel of cell lines we observed ubiquitous FRS2 and FRS3 transcript and protein expression in both benign and malignant cells. We next tested functional redundancy of FRS2 and FRS3 in prostate cancer cells. In DU145 cells, specific FRS2 suppression inhibited FGF induced signalling. This effect was not apparent in cells stably over-expressing FRS3. Indeed FRS3 over-expression resulted in enhanced proliferation (p = 0.005) compared to control cells. Given this functional redundancy, we tested the therapeutic principle of dual targeting of FRS2 and FRS3 in prostate cancer. Co-suppression of FRS2 and FRS3 significantly inhibited ERK activation with a concomitant reduction in cell proliferation (p < 0.05), migration and invasion (p < 0.05). Synchronous knockdown of FRS2 and FRS3 with exposure to cytotoxic irradiation resulted in a significant reduction in prostate cancer cell survival compared to irradiation alone (p < 0.05). Importantly, this synergistic effect was not observed in benign cells. Finally, we investigated expression of FRS2 and FRS3 transcript in a cohort of micro-dissected tumors of different grades as well as by immunohistochemistry in clinical biopsies. Here, we did not observe any difference in expression between benign and malignant biopsies.ConclusionsThese results suggest functional overlap of FRS2 and FRS3 in mediating mitogenic FGF signalling in the prostate. FRS2 and FRS3 are not over-expressed in tumours but targeted dual inhibition may selectively adversely affect malignant but not benign prostate cells.
Highlights
Fibroblast Growth Factor (FGF) receptor substrates (FRS2 and FRS3) are key adaptor proteins that mediate FGF-FGF receptors (FGFR) signalling in benign as well as malignant tissue
Functional redundancy of FRS2 and FRS3 in prostate cancer cells A panel of cell lines was first analysed by real time PCR to define expression levels in prostate cells
FRS2 and FRS3 mRNA were ubiquitously expressed in normal epithelial prostate cell lines (PNT1A/PNT2) and prostate cancer cell lines (LNCaP, DU145 and PC3) (Figure 1A)
Summary
FGF receptor substrates (FRS2 and FRS3) are key adaptor proteins that mediate FGF-FGFR signalling in benign as well as malignant tissue. In prostate cancer many FGF ligands and FGF receptors (FGFR) have been shown to be significantly over-expressed [4,5,6,7,8]. FRS2 binds to FGFRs, and to the TrkA, VEGF and RET receptors suggesting a broad role in signal transduction [11,12]. Ectopic expression of FRS3 in fibroblast derived from FRS2 -/-mouse embryos has been shown to rescue FGF induced ERK activation suggesting functional overlap in embryogenesis [18]. FRS3 has been proposed to have an important role in negative regulation of EGF receptor signalling [19,20] and recently has been reported as a novel microtubule-associated protein [21]
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