vasoactive-intestinal-peptide and Kidney-Neoplasms

Topics: Animals; Carcinoma, Renal Cell; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Male; Vasoactive Intestinal Peptide

We studied antitumor effect of VIP in human renal cell carcinoma (RCC) (A498 cells xenografted in immunosuppressed mice). VIP-treated cells gave resulted in p53 upregulation and decreased nuclear β-catenin translocation and NFκB expression, MMP-2 and MMP-9 activities, VEGF levels and CD-34 expression. VIP led to a more differentiated tubular organization in tumours and less metastatic areas. Thus, VIP inhibits growth of A498-cell tumours acting on the major issues involved in RCC progression such as cell proliferation, microenvironment remodelling, tumour invasion, angiogenesis and metastatic ability. These antitumoral effects of VIP offer new therapeutical possibilities in RCC treatment.

Topics: Active Transport, Cell Nucleus; Animals; beta Catenin; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Nucleus; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Male; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Vasoactive Intestinal Peptide

Molecular mechanisms involved in progression of clear-cell renal-cell carcinomas (ccRCCs) are poorly understood. A common genetic mutation found in ccRCC is the loss of the von Hippel-Lindau (VHL) gene, which contributes to cancer progression and metastasis. We investigated VIP effects on metastatic and angiogenic factors in human VHL-null A498 ccRCC and HK2 renal cells. VIP increased adhesion but decreased expression of metalloproteinases, MMP2 and MMP9, as well as cell migration and VEGF expression and secretion in A498 but not in HK2 cells. VIP enhanced ROS levels and decreased nuclear levels of β-catenin and NFκB p50-subunit in A498 cells, suggesting neuropeptide involvement in the observed decrease of metastatic ability in clear-cell carcinoma. VIP effects in A498 cells were blocked by the VPAC(1/2)-receptor antagonist JV-1-53. In conclusion, present data point to a role of VIP in preventing invasion and metastasis in ccRCCs and support its potential therapeutic usefulness in this disease.

Topics: Antineoplastic Agents; beta Catenin; Cadherins; Carcinoma, Renal Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Humans; Kidney Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; NF-kappa B p50 Subunit; Oxidative Stress; Reactive Oxygen Species; Vascular Endothelial Growth Factor A; Vasoactive Intestinal Peptide

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.

Topics: Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cyclic AMP; Gene Expression Regulation, Neoplastic; Humans; Intracellular Space; Kidney Neoplasms; Mice; Mice, Nude; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Polypeptide, Type I; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Vasoactive Intestinal Peptide; Xenograft Model Antitumor Assays