Vasoactive intestinal peptide (VIP) inhibits human renal cell carcinoma proliferation

Abstract

Clear renal cell carcinoma (cRCC) is an aggressive and fatal neoplasm. The present work was undertaken to investigate the antiproliferative potential of vasoactive intestinal peptide (VIP) exposure on non-tumoral (HK2) and tumoral (A498, cRCC) human proximal tubular epithelial cell lines. Reverse transcription and semiquantitative PCR was used at the VIP mRNA level whereas enzyme immunoanalysis was performed at the protein level. Both renal cell lines expressed VIP as well as VIP/pituitary adenylate cyclase-activating peptide (VPAC) receptors whereas only HK2 cells expressed formyl peptide receptor-like 1 (FPRL-1). Receptors were functional, as shown by VIP stimulation of adenylyl cyclase activity. Treatment with 0.1μM VIP (24h) inhibited proliferation of A498 but not HK2 cells as based on a reduction in the incorporation of [(3)H]-thymidine and BrdU (5'-Br-2'-deoxyuridine), PCNA (proliferating-cell nuclear antigen) expression and STAT3 (signal transducer and activator of transcription 3) expression and activation. VPAC(1)-receptor participation was established using JV-1-53 antagonist and siRNA transfection. Growth-inhibitory response to VIP was related to the cyclic adenosine monophosphate (cAMP)/exchange protein directly activated by cAMP (EPAC)/phosphoinositide 3-kinase (PI3-K) signaling systems as shown by studies on adenylate cyclase stimulation, and using the EPAC-specific compound 8CPT-2Me-cAMP and specific kinase inhibitors such as H89, wortmannin and PD98059. The efficacy of VIP on the prevention of tumor progression was confirmed in vivo using xenografted athymic mouse. These actions support a potential role of this peptide and its agonists in new therapies for cRCC.

The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention

“…It is reported that in A172 and U87MG human glioblastoma cells, PKA and EPAC1 pathways synergistically promote cAMP-induced cell death and cell cycle arrest [34], while in clear renal cell carcinoma (cRCC) A498 cells, growth-inhibitory response to vasoactive intestinal peptide (VIP) is shown to be mediated by EPAC/PI3K pathway [35]. In contrast, EPAC1 promotes cell proliferation and survival by up-regulating Ras/MAPK and PI3K/AKT/mTOR signaling in prostate cancer cells [36,37].…”

Examination of PACAP-Like Immunoreactivity in Urogenital Tumor Samples

“…There are several data indicating nephroprotective effects of PACAP against different toxic agents , such as oxidative stress (Horvath et al 2010a, kidney ischemia (Szakaly et al 2008;Horvath et al 2010b), diabetes (Banki et al 2013(Banki et al , 2014, myeloma- (Arimura et al 2006a, b;Li et al 2007), gentamicin- (Li et al 2008), cisplatin-(Li et al 2011, and cyclosporine A-induced nephropathy ), but we have only few data about its effect in kidney tumors. Recently, Vacas et al (2012) demonstrated that VIP and VPAC1 receptors are expressed in tumoral human proximal tubular epithelial cell line and VIP is able to prevent tumor progression. PACAP shows very close similarity to VIP, therefore, we suggest that it could have a potential role in the development of kidney tumors.…”

Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma

“…Hence local inhibition of peptidergic system in papillary type RCC may partly be responsible from resistance to immunotherapy. Furthermore NEP-induce hydrolysis of VIP creates selective VPAC-1 receptor agonist which has anti-proliferative and antiinflammatory effects [36]. Hence loss of NEP activity may prevent anti-tumoral effects of VIP on RCC.…”