atrial-natriuretic-factor and Prostatic-Neoplasms

It was well established that the atrial natriuretic peptide (ANP)/natriuretic peptide receptor-A (NPRA) signaling pathway controls natriuretic, diuretic, vasorelaxant, and anti-proliferative responses in the regulation of the human cardiovascular system by previous studies. Yet in recent years, more and more evidence has shown that the ANP/NPRA signaling pathway plays an important role in human cancer. For example, NPRA is abundantly expressed on tumorigenic mouse and human prostate cancer (PCa) cells, but not in nontumorigenic prostate epithelial cells and down-regulation of NPRA-induced apoptosis in PCa cells. Dexamethasone can increase the expression of ANP markedly, and that is the reason why dexamethasone is the cornerstone in the treatment of multiple myeloma. NPRA deficiency can substantially protect C57BL/6 mice from lung, skin, and ovarian cancers. These results strongly suggest ANP and NPRA may play an anti-cancer and carcinogenesis role, respectively, and this signaling pathway could be a more potent target for cancer therapy. In light of these new insights, this review will summarize the structures, functions, and their regulation by cell signaling, and their different impacts on tumors.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Cell Transformation, Neoplastic; Down-Regulation; Female; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Molecular Targeted Therapy; Neoplasms; Prostatic Neoplasms; Receptors, Atrial Natriuretic Factor; Signal Transduction

Inflammation, by inducing a tumor-promoting microenvironment, is a hallmark for prostate cancer (PCa) progression. NOD-like receptor protein 3 (NLRP3)-inflammasome activation, interleukin-1β (IL-1β) secretion, and cancer cell-released extracellular vesicles (EVs) contribute to the establishment of tumor microenvironment. We have shown that PC3-derived EVs (PC3-EVs) activate inflammasome cascade in non-cancerous PNT2 cells. It is known that the endogenous biomolecules and Natriuretic Peptides (NPs), such as ANP and BNP, inhibit inflammasome activation in immune cells. Here we investigated whether ANP and BNP modify PCa inflammatory phenotype in vitro. By using PNT2, LNCaP, and PC3 cell lines, which model different PCa progression stages, we analyzed inflammasome activation and the related pathways by Western blot and IL-1β secretion by ELISA. We found that tumor progression is characterized by constitutive inflammasome activation, increased IL-1β secretion, and reduced endogenous NPs expression. The administration of exogenous ANP and BNP, via p38-MAPK or ERK1/2-MAPK, by inducing NLRP3 phosphorylation, counteract inflammasome activation and IL-1β maturation in PC3 and PC3-EVs-treated PNT2 cells, respectively. Our results demonstrate that NPs, by interfering with cell-specific signaling pathways, exert pleiotropic anti-inflammatory effects converging toward inflammasome phosphorylation and suggest that NPs can be included in a drug repurposing process for PCa.

Topics: Antineoplastic Agents; Atrial Natriuretic Factor; Cell Line, Tumor; Humans; Inflammation; Male; MAP Kinase Signaling System; Natriuretic Peptide, Brain; Neoplasm Proteins; Prostatic Neoplasms

Atrial natriuretic peptide has been recently discovered to have anticancer effects via interaction with cell surface natriuretic peptide receptor A (NPRA) and natriuretic peptide clearance receptor (NPRC). In a preclinical model, NPRA expression has been identified during tumor angiogenesis and may serve as a potential prognostic marker and target for prostate cancer (PCa) therapy. However, the presence of NPRC receptor in the PCa model has not yet been assessed. Furthermore, there is still no report using nanoparticle for PCa positron emission tomography (PET) imaging. Herein, an amphiphilic comb-like nanoparticle was synthesized with controlled properties through modular construction containing C-atrial natriuretic factor (CANF) for NPRC receptor targeting and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator for high specific activity Cu-64 radiolabeling. The pharmacokinetics of (64)Cu-CANF-Comb exhibited tuned biodistribution and optimized in vivo profile in contrast to the nontargeted (64)Cu-Comb nanoparticle. PET imaging with (64)Cu-CANF-Comb in CWR22 PCa tumor model showed high blood pool retention, low renal clearance, enhanced tumor uptake, and decreased hepatic burden relative to the nontargeted (64)Cu-Comb. Immunohistochemistry staining confirmed the presence of NPRC receptor in tumor tissue. Competitive PET receptor blocking study demonstrated the targeting specificity of (64)Cu-CANF-Comb to NPRC receptor in vivo. These results establish a new nanoagent for prostate cancer PET imaging.

Topics: Animals; Atrial Natriuretic Factor; Copper Radioisotopes; Heterocyclic Compounds, 1-Ring; Immunohistochemistry; Male; Mice; Mice, Nude; Nanoparticles; Positron-Emission Tomography; Prostate; Prostatic Neoplasms; Receptors, Atrial Natriuretic Factor

Vascular endothelial growth factor (VEGF) helps control tumour growth via causing new capillaries growth in tumours. Four cardiac hormones [i.e. vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide (KP) and atrial natriuretic peptide (ANP)] that eliminate up to up to 86% of human small-cell lung cancers growing in mice were investigated for their effects on VEGF and the VEGFR2/KDR/Flk-1 receptor. The VEGFR2 receptor is the main receptor mediating VEGF's cancer-enhancing effects.. Four cardiac hormones were evaluated for their ability to decrease VEGF/VEGFR2 measured by ELISAs in three human cancer cell lines.. Vessel dilator, LANP, KP and ANP, over a concentration range of 100 pM to 10 μM, maximally decreased the VEGFR2 receptor in human pancreatic adenocarcinoma cells by 48%, 49%, 74% and 83%. Vessel dilator, LANP, KP and ANP decreased the VEGFR2 receptor by 77%, 89%, 88% and 67% in human small-cell lung cancer cells and by 48%, 92%, 64% and 71% in human prostate cancer cells. These results were confirmed with the cardiac hormones also decreasing the VEGFR2 receptor measured by Western blots. VEGF itself in pancreatic carcinoma cells was decreased by 42%, 58%, 36% and 40% by vessel dilator, LANP, KP and ANP. VEGF levels were decreased 25%, 23%, 17% and 23% in small-cell lung cancer cells and decreased by 24%, 20%, 23% and 24% in prostate cancer cells by vessel dilator, LANP, KP and ANP.. Four cardiac hormones are the first dual inhibitors of VEGF and the VEGFR2/KDR/Flk-1 receptor.

Topics: Angiogenesis Inhibitors; Atrial Natriuretic Factor; Blotting, Western; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Humans; Lung Neoplasms; Male; MAP Kinase Signaling System; Neoplasm Transplantation; Pancreatic Neoplasms; Peptide Fragments; Prostatic Neoplasms; Protein Precursors; Small Cell Lung Carcinoma; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Four cardiac hormones, namely, vessel dilator, long-acting natriuretic peptide, atrial natriuretic peptide and kaliuretic peptide, have anticancer effects but whether they cause cell death of human cancer cells or normal cells is unknown.. These cardiac hormones were examined for their ability to cause cell death quantified by measurement of nuclear matrix proteins 41/7 which is a function of the number of dead or dying cells.. Each of these cardiac hormones caused cell death in up to 36% (p < 0.0001) of the pancreatic adenocarcinoma cells and up to 28% (p<0.0001) of the prostate cancer cells over a concentration range of 100 pmol/l to 10 μmol/l. There was no cell death of normal human prostate, kidney, or lung cells at the above concentrations.. Four cardiac hormones cause death of pancreatic and prostate cancer cells but not of normal prostate, lung, or kidney cells.

Topics: Adenocarcinoma; Aged; Antigens, Nuclear; Atrial Natriuretic Factor; Cell Cycle Proteins; Cell Death; Cell Line; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Kidney; Lung; Male; Nuclear Matrix-Associated Proteins; Pancreatic Neoplasms; Peptide Fragments; Prostate; Prostatic Neoplasms; Protein Precursors

Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, have anticancer effects in vitro and in vivo. Epidermal growth factor's mechanism of cancer formation involves the activation of Ras.. These four cardiac hormones were evaluated for their ability to inhibit mitogen (epidermal growth factor) activation of Ras.. Epidermal growth factor increased the activation of Ras by 68%, 85% and 90% at its 1, 2 and 5 ng mL(-1) concentrations. Vessel dilator, long-acting natriuretic peptide, atrial natriuretic peptide and kaliuretic peptide inhibited 5 ng mL(-1) epidermal growth factor's stimulation of Ras by 73%, 79%, 33% and 45%, respectively, at their 1 microM concentrations. Their effects on epidermal growth factor's activation of Ras were specific with addition of the cardiac hormones' respective antibodies (5 microM) blocking 95%, 93%, 100% and 100% (P < 0.001 for each) of their ability to inhibit epidermal growth factor's stimulation of Ras.. Four cardiac hormones specifically inhibit epidermal growth factor's activation of Ras. This investigation would suggest that these cardiac hormones' anticancer effects involve the inhibition of mitogens such as epidermal growth factor's ability to activate Ras as well as inhibiting unstimulated basal activity of Ras.

Topics: Adenocarcinoma; Antineoplastic Agents; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Epidermal Growth Factor; Genes, ras; Humans; Male; Prostatic Neoplasms

Vessel dilator and kaliuretic peptide have anticancer effects in human prostate adenocarcinomas.. The effects of vessel dilator, kaliuretic peptide and cyclic GMP on Ras were examined in human prostate adenocarcinoma cells.. Vessel dilator and kaliuretic peptide decreased the activation of Ras -GTP over a concentration range of 0.01 microM to 1 microM. Vessel dilator and kaliuretic peptide (each 1 muM) inhibited the phosphorylation of Ras by 95% (p<0.0001) and 90% (p<0.0001), respectively. At 0.01 microM of kaliuretic peptide, the maximal inhibition was 95% . The inhibition of Ras lasted for 48 to 72 hours secondary to both peptides. Their ability to inhibit Ras was inhibited by cyclic GMP antibody and cyclic GMP itself inhibited Ras phosphorylation (89%; p=0.0015).. Vessel dilator and kaliuretic peptide both inhibit Ras partially mediated via cyclic GMP as part of their anticancer mechanism(s) of action.

Topics: Adenocarcinoma; Aged; Atrial Natriuretic Factor; Cyclic GMP; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Diphosphate; Humans; Immunoblotting; Male; Natriuresis; Peptide Fragments; Prostatic Neoplasms; Protein Precursors; ras Proteins; Sodium-Potassium-Exchanging ATPase; Tumor Cells, Cultured

Atrial natriuretic peptide and long-acting natriuretic peptide have anticancer effects in human prostate adenocarcinoma.. The effects of atrial natriuretic peptide and long-acting natriuretic peptide and cyclic GMP on Ras were examined in human prostate adenocarcinoma cells.. Atrial natriuretic peptide and long-acting natriuretic peptide reduced the activation of Ras-GTP over a concentration range of 0.01 microM to 1 microM. Atrial natriuretic peptide and long-acting natriuretic peptide (each 0.1 microM) inhibited the phosphorylation of Ras 90% (p<0.0001) and 83% (p<0.0001), respectively. At 0.01 microM of long-acting natriuretic peptide, the maximal inhibition was 89%, which occurred within 5 minutes. Both peptide hormones inhibited Ras for 24 hours. Their ability to inhibit Ras was inhibited by cyclic GMP antibody and cyclic GMP itself inhibited Ras phosphorylation (72%; p=0.009).. Atrial natriuretic peptide and long-acting natriuretic peptide both inhibit Ras partially mediated via cyclic GMP as part of their anticancer mechanism(s) of action.

Topics: Adenocarcinoma; Aged; Atrial Natriuretic Factor; Blotting, Western; Cyclic GMP; Humans; Immunoblotting; Immunoprecipitation; Male; Peptide Fragments; Phosphorylation; Prostatic Neoplasms; ras Proteins

Low tumor oxygenation (hypoxia) correlates with resistance to chemotherapeutic agents. We recently reported that in vitro hypoxia induced resistance to various anti-cancer drugs can be attenuated by nitric oxide mimetic agents. Natriuretic peptides are molecules that mediate their cellular effects by activating a signaling pathway similar to that activated by nitric oxide. In the current study we determined whether atrial natriuretic peptide is able to inhibit hypoxia induced chemoresistance in prostate carcinoma cells.. Reverse transcriptase-polymerase chain reaction and atrial natriuretic peptide binding studies were used to determine the presence and function of natriuretic peptide receptors on a panel of human cell lines as well as in tissue samples. Drug sensitivity assays of cell lines exposed to hypoxic or standard conditions were performed in the presence of various concentrations of atrial natriuretic peptide.. These studies revealed the presence of the 3 known natriuretic peptide receptors A, B and C in PC-3 and DU-145 human prostate carcinoma cells (American Type Culture Collection, Manassas, Virginia) as well as in tissue samples of human prostate cancer. Atrial natriuretic peptide binding to these cells was unaffected by culture in 0.5% vs 20% O(2). Clonogenic assays revealed that incubation of these cells in 0.5% O(2) for 24 hours resulted in a subsequent 4 to 10-fold increase in their survival following 1-hour exposure to doxorubicin (Sigma) (12.5 microM) (p <0.001). While small concentrations of atrial natriuretic peptide (10(-7) to 10(-13) M) did not affect sensitivity to doxorubicin in cells incubated in 20% O(2), similar concentrations of atrial natriuretic peptide inhibited the survival of these cells incubated in 0.5% O(2) by up to 50% (p <0.006). Using the cyclic guanosine monophosphate dependent protein kinase G inhibitor KT5823 (15 microM) the chemosensitizing effect of atrial natriuretic peptide was abrogated.. These results indicate the potential use of natriuretic peptides as adjuvants to chemotherapy for prostate cancer.

Topics: Adenocarcinoma; Atrial Natriuretic Factor; Cell Hypoxia; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms; Tumor Cells, Cultured

Mortality from prostate cancer remains a significant problem with current treatment(s), with an expected 30 350 deaths from prostate cancer in 2005. Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide and atrial natriuretic peptide have significant anticancer effects in breast and pancreatic adenocarcinomas. Whether these effects are specific and whether they have anticancer effects in prostate adenocarcinoma cells has not been determined.. These peptide hormones were evaluated to determine if they have specific anticancer effects in human prostate adenocarcinomas.. Dose-response curves revealed a significant (P < 0.05) decrease in human prostate cancer number with each tenfold increase in the concentration from 1 microM to 1000 microM (i.e. 1 mM) of these four peptide hormones. There was a 97.4%, 87%, 88% and 89% (P < 0.001 for each) decrease in prostate cancer cells secondary to vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and atrial natriuretic peptide, respectively, at their 1-mM concentrations within 24 h, without any proliferation in the 3 days following this decrease. These same hormones decreased DNA synthesis from 68% to 89% (P < 0.001). When utilized with their respective antibodies their ability to decrease prostate adenocarcinoma cells or inhibit their DNA synthesis was completely blocked. Western blots revealed that for the first time natriuretic peptide receptors (NPR) A- and C- were present in prostate cancer cells.. These results indicate that these peptide hormones' anticancer effects are specific. Furthermore, they have very potent effects of eliminating up to 97% of prostate cancer cells within 24 h of treatment.

Topics: Adenocarcinoma; Antineoplastic Agents; Atrial Natriuretic Factor; Cell Count; Cell Line, Tumor; DNA, Neoplasm; Dose-Response Relationship, Drug; Guanylate Cyclase; Humans; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Peptide Fragments; Prostatic Neoplasms; Protein Precursors; Receptors, Atrial Natriuretic Factor