Abstract
Neuropilin-1 (NRP1), a non–tyrosine kinase receptor, is overexpressed in many cancers including pancreatic and lung cancers. Inhibition of NRP1 expression, however, has differing pro-tumor vs. anti-tumor effects, depending on the cancer types. To understand the differential role of NRP1 in tumorigenesis process, we utilized cells from two different cancer types, pancreatic and lung, each containing either wild type KRAS (KRASwt) or mutant KRAS (KRASmt). Inhibition of NRP1 expression by shRNA in both pancreatic and lung cancer cells containing dominant active KRASmt caused increased cell viability and tumor growth. On the contrary, inhibition of NRP1, in the tumor cells containing KRASwt showed decreased tumor growth. Importantly, concurrent inhibition of KRASmt and NRP1 in the tumor cells reverses the increased viability and leads to tumor inhibition. We found that NRP1 shRNA expressing KRASmt tumor cells caused increased cell viability by decreasing SMAD2 phosphorylation. Our findings demonstrate that the effects of NRP1 knockdown in cancer cells are dependent on the genetic status of KRAS.
Highlights
Neuropilin-1 (NRP1) is a non–tyrosine kinase receptor involved in neuronal guidance and angiogenesis[1,2]
After NRP1 knockdown, viability was increased in PDAC and non–small cell lung cancer (NSCLC) cancer cell lines with KRASmt, PANC-1 and A549 respectively and was decreased in cells with KRASwt, BxPC-3 and H226 respectively (Fig. 1B–E)
These results indicate that NRP1 has distinct viability effects between different PDAC and NSCLC cancer cell lines
Summary
Neuropilin-1 (NRP1) is a non–tyrosine kinase receptor involved in neuronal guidance and angiogenesis[1,2]. Recent studies have shown that NRP1 is multifunctional and capable of binding multiple growth factors and mediators, including integrins, fibroblast growth factors, transforming growth factor β-1 (TGFβ1) and its receptors, hepatocyte growth factor and its receptor c-Met, and platelet-derived growth factor and its receptors[3,4] These interactions link NRP1 to multiple pathways including tumorigenesis and angiogenesis. In cancer cells harboring KRASmt, NRP1 down regulation promotes tumorigenesis through the suppression of SMAD2 pathway. These novel findings provide an opportunity to tailor precise, individualized therapies for effective cancer treatment
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