Silencing of RON Receptor Signaling Promotes Apoptosis and Gemcitabine Sensitivity in Pancreatic Cancers

Abstract

The RON receptor tyrosine kinase is overexpressed in premalignant pancreatic intraepithelial neoplasia (PanIN) and in the majority of pancreatic cancers. In pancreatic cells, RON is an important K-Ras effector and RON ligand can enhance migration/invasion and apoptotic resistance. However, the pathobiological significance of RON overexpression in pancreatic cancers has yet to be fully established. In this study, we demonstrate that RON signaling mediates a unique transcriptional program that is conserved between cultured cells derived from murine PanIN or human pancreatic cancer cells grown as subcutaneous tumor xenografts. In both systems, RON signaling regulates expression of genes implicated in cancer-cell survival, including Bcl-2 and the transcription factors signal transducer and activator of transcription 3 (STAT 3) and c-Jun. shRNAmediated silencing of RON in pancreatic cancer xenografts inhibited their growth, primarily by increasing susceptibility to apoptosis and by sensitizing them to gemcitabine treatment. Escape from RON silencing was associated with re-expression of RON and/or expression of phosphorylated forms of the related c-Met or epidermal growth factor receptors. These findings indicate that RON signaling mediates cell survival and in vivo resistance to gemcitabine in pancreatic cancer, and they reveal mechanisms through which pancreatic cancer cells may circumvent RON-directed therapies.

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

“…Previous studies have shown that RON is overexpressed and activated in primary PDAC samples and established cell lines (1)(2)(3)(4)(5)(6). Here, we determined the therapeutic effect of BMS-777607 on RON signaling in L3.6pl cells and CSCs þ24/44/ESA .…”

“…Aberrant RON expression also regulates PDAC cell migration, survival, and invasion through multiple signaling pathways (4-6, 9, 10). In certain PDAC cell lines, knockdown of RON expression by specific siRNA causes PDAC cell apoptosis and increase their sensitivity in response to chemotherapeutics (4). These preclinical studies indicate that aberrant RON signaling is critical for PDAC cell growth and survival.…”

“…Overexpression of the recepteur d'origine nantais (RON) receptor tyrosine kinase (RTK) in cancer cells has been implicated in tumorigenic activities and malignant progression (1)(2)(3)(4). Aberrant RON expression also has been molecularly targeted in mouse xenograph models of pancreatic ductal adenocarcinoma (PDAC; refs.…”

“…Moreover, anti-RON antibodies have been used as a drug delivery method to improve chemotherapeutic efficacy (13). Currently, several TKIs, including PHA665752, compound-I, and BMS-777607, that target RON signaling have been characterized in a preclinical model (4)(5)(6)(14)(15)(16). BMS-777607 is a MET superfamily inhibitor with a high specificity to RON at the enzymatic IC 50 of 1.8 nmol/L (16).…”

Effects of PTCs on nonsense-mediated mRNA decay are dependent on PTC location

“…The RON gene encodes the macrophage-stimulating protein (MSP) 1 receptor (1). The activation of RON by MSP induces tumor progression and invasion, whereas the inactivation of RON promotes cell apoptosis (2)(3)(4). RON is a heterodimeric protein with a disulfide bond linking a 40-kDa α chain, containing the extracellular domain for ligand binding, and a 150-kDa β chain, incorporating the intracellular kinase domain and a transmembrane domain (5,6).…”