Neuropeptide Levels as well as Neprilysin Activity

Authors: Nuray Erin Tümay İpekçi Bahar Akkaya İrem Hicran Özbudak Mehmet Baykara

Publish Date: 2016/10/19

Volume: 9, Issue: 2-3, Pages: 141-147

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Abstract

Calcitonin Generelated Peptide CGRP Vasoactive Intestinal Peptide VIP and Substance P SP are sensory neuropeptides which may alter cancer growth through modulation of chronic inflammation We recently reported that SP suppresses breast cancer growth and metastasis through neuroimmune modulation These neuropeptides are hydrolyzed by Neprilysin NEP to bioactive fragments Decreased activity of NEP was reported in clear cell and chromophobe type renal cell carcinoma RCC It is however not known how the levels of neuropeptides hydrolyzed with NEP changes in RCC Decrease activity of SP and CGRP containing sensory nerve endings was previously reported to increase cancer metastasis in animal models It is however not known how peptidergic nerve endings are altered in RCC Hence we here evaluated the levels of neuronal and nonneuronal neuropeptides and NEP activity in RCC including papillary type as well as neighboring uninvolved kidney A crosssectional study was conducted in 57 patients undergoing radical nephrectomy and diagnosed with RCC NEP activity levels and expression were determined using flourogenic substrate western blot and qPCR respectively in freshlyfrozen tissues Immunohistochemical analyses were also performed Neuronal and nonneuronal levels of CGRP SP and VIP levels were determined using twostep acetic acid extraction Levels and activity of NEP were markedly decreased in RCC regardless of subtype Similar levels of VIP were detected in first and second extractions VIP levels were higher in clear cell and papillary RCC compared to nearby kidney tissue VIP levels of neighboring kidney tissue of papillary type RCC was significantly lower compared to kidney samples from clear cell RCC CGRP levels were higher in second extraction Similar to VIP levels CGRP levels of neighboring kidney tissue from clear cell and chromophobe type RCC was significantly lower compared to corresponding tumor samples an effect observed in the second extraction VIP and CGRP levels of nearby kidney tissue varied subtype dependently demonstrating that different subtypes of RCC alter their local environment differently Furthermore NEPinduce hydrolysis of VIP creates selective VPAC1 receptor agonist which has antiproliferative and antiinflammatory effects Hence loss of NEP activity may prevent antitumoral effects of VIP on RCCThis work was supported by funds from Akdeniz University Research Unit Antalya Turkey Grant no 2009010103005 Experiments were preformed in part in Health Sciences Research Center of Akdeniz University SBAUM Authors thank to Mrs Özlem Duymuş and Mr Onur Yılmaz for providing technical assistance

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