Abstract
An essential feature of cancer is dysregulation of cell senescence and death. Renalase, a recently discovered secreted flavoprotein, provides cytoprotection against ischemic and toxic cellular injury by signaling through the PI3K-AKT and MAPK pathways. Here we show that renalase expression is increased in pancreatic cancer tissue and that it functions as a growth factor. In a cohort of patients with pancreatic ductal adenocarcinoma, overall survival was inversely correlated with renalase expression in the tumor mass, suggesting a pathogenic role for renalase. Inhibition of renalase signaling using siRNA or inhibitory anti-renalase antibodies decreased the viability of cultured pancreatic ductal adenocarcinoma cells. In two xenograft mouse models, either the renalase monoclonal antibody m28-RNLS or shRNA knockdown of renalase inhibited pancreatic ductal adenocarcinoma growth. Inhibition of renalase caused tumor cell apoptosis and cell cycle arrest. These results reveal a previously unrecognized role for the renalase in cancer: its expression may serve as a prognostic maker and its inhibition may provide an attractive therapeutic target in pancreatic cancer.
Highlights
Using biotin transfer studies with RP-220 in the human proximal tubular cell line HK-2 and protein identification by mass spectrometry, we identified PMCA4b as a renalase binding protein
Since RNLS functions as a survival factor that engages the MAPK and PI3K pathways that are disordered in pancreatic cancer, and because its expression is regulated by the signal transducer and activator of transcription STAT315, we postulated that abnormal regulation of RNLS expression and signaling could provide a survival advantage to cancer cells, and promote tumor formation[16]
RNLS expression was elevated in both pancreatic ductal adenocarcinoma cell (PDAC) (~3 fold) and neuroendocrine (8 fold) tumors (Fig. 1B)
Summary
RNLS overexpression in PDAC and association with decreased survival. To determine if RNLS expression differed between normal and cancer tissue, we examined fifteen different types of cancer by screening commercially available human tissue cDNA arrays using quantitative PCR (qPCR). To determine the functional consequences of inhibiting RNLS expression and signaling in pancreatic cancer cells, the effect of decreasing RNLS expression on cell viability in vitro was evaluated by RNLS knockdown using siRNA This treatment markedly reduced the viability of the PDAC lines Panc[1] and MiaPaCa2 (Fig. 2A and Supplement Fig. 4S). Sections of BxPC3 xenografted tumors from mice treated with either rabbit IgG or m28-RNLS revealed a ~2-fold increase in apoptosis (TUNEL staining) (Fig. 3A, top left panels) in the antibody-treated tumors: m28-RNLS vs IgG; 28.4 ± 3.3 positive cells/high power field vs IgG- 14.8 ± 2.3, n = 14, p = 0.002. PMCA4b inhibition had no discernable effect on RNLS mediated STAT3 phosphorylation suggesting the existence of an additional RNLS receptor(s)
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