atrial-natriuretic-factor and Ovarian-Neoplasms

Dysregulated apoptosis plays a critical role in the development of a number of aberrant cellular processes, including tumorigenesis and chemoresistance. However, the mechanisms that govern the normal apoptotic program are not completely understood. Soluble guanylyl cyclase (sGC) and cyclic guanosine monophosphate (cGMP) promote mammalian cell viability via an unknown mechanism and p53 status is a key determinant of cell fate in human ovarian cancer cells. Whether an interaction exists between these two determinants of cell fate is unknown. We hypothesized that basal sGC activity reduces p53 content and attenuates p53-dependent apoptosis in human ovarian cancer cells. Suppression of sGC activity with the specific inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) lowered cGMP content, and increased p53 protein content and induced apoptosis in three ovarian cancer cell lines, effects which were attenuated by the cGMP analog 8-Br-cGMP and by Atrial Natriuretic Factor, an activator of particulate guanylyl cyclase, which circumvent the inhibition of sGC. ODQ prolonged p53 half-life, induced phosphorylation of p53 on Ser15, and upregulated the p53-dependent gene products p21, murine double minute-2, and the proapoptotic, p53-responsive gene product Bax. ODQ activated caspase-3, and ODQ-induced apoptosis was inhibited by overexpression of X-linked inhibitor of apoptosis Protein. Pretreatment with the specific p53 inhibitor pifithrin or downregulation of p53 using a specific small inhibitory RNA significantly attenuated ODQ-induced apoptosis. Moreover, ODQ-induced upregulation of p21 and Bax and ODQ-induced apoptosis were significantly reduced in a p53 mutant cell line relative to the wild-type parental cell line. Thus, the current study establishes that basal sGC/cGMP activity regulates p53 protein stability, content, and function, possibly by altering p53 phosphorylation and stabilization, and promotes cell survival in part through regulation of caspase-3 and p53.

Topics: Adenoviridae; Apoptosis; Atrial Natriuretic Factor; bcl-2-Associated X Protein; Benzothiazoles; Caspase 3; Caspases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclin-Dependent Kinase Inhibitor p21; Enzyme Activation; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Guanylate Cyclase; Half-Life; Humans; Mutation; Ovarian Neoplasms; Oxadiazoles; Phosphorylation; Proto-Oncogene Proteins c-mdm2; Quinoxalines; RNA, Small Interfering; Serine; Signal Transduction; Thiazoles; Toluene; Tumor Cells, Cultured; Tumor Suppressor Protein p53; X-Linked Inhibitor of Apoptosis Protein

To determine whether plasma atrial natriuretic factor (ANF) levels are different in patients with gynecologic malignancy compared with those in healthy, nonpregnant women, and if differences do exist, whether chemotherapy plays a role.. We compared the plasma levels of ANF in nonpregnant women free of malignancy (group 1, n = 25) and in patients with malignancy receiving at least one course of platinum-based chemotherapy (group 2, n = 32). To differentiate the contributory role of chemotherapy, another group of patients (group 3, n = 18) was studied before the initiation of chemotherapy.. The ANF values (mean +/- standard error [SE]) in groups 1, 2, and 3 were 7.3 +/- 0.3, 13.8 +/- 0.8, and 14.6 +/- 1.8 fmol/mL of plasma, respectively. Significant differences (P < or = .001) occurred between groups 1 and 2 and 1 and 3, but not between 2 and 3. In comparing groups 2 and 3 for a specific type of cancer, there were no significant differences. The respective values (mean +/- SE) for endometrial, ovarian, and cervical cancer before chemotherapy were 9.9 +/- 1.7, 15.05 +/- 2.6, and 18.5 +/- 4.3 fmol/mL. After chemotherapy, the values remained at 9.3 +/- 1.5, 15.03 +/- 1.06, and 14.6 +/- 2.2 fmol/mL, respectively.. Plasma ANF levels in gynecologic cancer patients were significantly higher than those in healthy, nonpregnant women. Levels were higher before chemotherapy started, thus negating the idea that chemotherapy may initiate the production and release of ANF.

Topics: Adult; Atrial Natriuretic Factor; Endometrial Neoplasms; Female; Humans; Middle Aged; Ovarian Neoplasms; Platinum Compounds; Uterine Cervical Neoplasms

We have compared the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) genes in various human tissues using a quantitative polymerase chain reaction technique. Tissues of three human subjects, obtained at autopsy, were analyzed. BNP transcripts could be detected in the central nervous system, lung, thyroid, adrenal, kidney, spleen, small intestine, ovary, uterus, and striated muscle. ANP transcripts could also be demonstrated in various human extracardiac tissues including several endocrine organs. In all peripheral tissues, the level of both natriuretic peptide transcripts was approximately 1-2 orders of magnitude lower than in cardiac ventricular tissues. This distribution is in marked contrast to the much lower level of ANP and BNP transcripts present in extracardiac rat tissues (generally less than 1/1000 of ventricles). These data suggest differential expression of the two natriuretic peptide genes in cardiac and extracardiac tissues in man. Furthermore, the presence of local synthesis of ANP and BNP in various peripheral organs suggests paracrine and/or autocrine function of these natriuretic peptides.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Brain; Cardiomegaly; DNA Primers; Female; Gene Expression; Humans; Liver; Lung; Male; Middle Aged; Molecular Sequence Data; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Organ Specificity; Ovarian Neoplasms; Ovary; Pancreas; Pituitary Gland; Polymerase Chain Reaction; Rats; Transcription, Genetic