Regulation of glutathione synthesis

IL-8, a member of the chemokine family, has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to determine the mechanism of IL-8-mediated angiogenesis. We examined the direct role of IL-8 in angiogenesis by examining IL-8 receptor expression on endothelial cells and their proliferation, survival, and matrix metalloproteinases (MMPs) production. We demonstrate that HUVEC and human dermal microvascular endothelial cells constitutively express CXCR1 and CXCR2 mRNA and protein. Recombinant human IL-8 induced endothelial cell proliferation and capillary tube organization while neutralization of IL-8 by anti-IL-8 Ab blocks IL-8-mediated capillary tube organization. Incubation of endothelial cells with IL-8 inhibited endothelial cell apoptosis and enhanced antiapoptotic gene expression. Endothelial cells incubated with IL-8 had higher levels of Bcl-x L :Bcl-x S and Bcl-2:Bax ratios. Furthermore, incubation of endothelial cells with IL-8 up-regulated MMP-2 and MMP-9 production and mRNA expression. Our data suggest that IL-8 directly enhanced endothelial cell proliferation, survival, and MMP expression in CXCR1- and CXCR2-expressing endothelial cells and regulated angiogenesis.

IL-8 Directly Enhanced Endothelial Cell Survival, Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis

Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties.

Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect

Glutathione (GSH) is an important intracellular peptide with multiple functions ranging from antioxidant defense to modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the avail- ability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, g-glu- tamylcysteine synthetase (GCS). In the liver, major factors that determine the availability of cysteine are diet, membrane transport activities of the three sulfur amino acids cysteine, cystine and methionine, and the conversion of methionine to cysteine via the trans-sulfuration pathway. Many conditions alter GSH level via changes in GCS activity and GCS gene expression. These include oxidative stress, activators of Phase II detoxifying enzymes, antioxidants, drug- resistant tumor cell lines, hormones, cell prolifera- tion, and diabetes mellitus. Since the molecular cloning of GCS, much has been learned about the regulation of this enzyme. Both transcriptional and post-transcriptional mechanisms modulate the activ- ity of this critical cellular enzyme.—Lu, S. C. Regu- lation of hepatic glutathione synthesis: current con- cepts and controversies. FASEB J. 13, 1169 -1183 (1999)

Regulation of hepatic glutathione synthesis: current concepts and controversies

Elevation of Circulating Interleukin 6 After Surgery: Factors Influencing the Serum Level

https://www.gastrojournal.org/article/0016-5085(89)91488-1/pdf

Inhibition of stress-induced gastric injury in the rat by glutathione.

Serum levels of group II phospholipase A2 (PLA2) have been reported to be associated with stage of disease in cancer patients. These levels are also related to the malignant potential in tissues, and are an important prognostic factor. We radioimmunoassayed group II PLA2 levels in pleural and peritoneal effusions from patients with various cancers. We also investigated the production of group II PLA2 in cells in effusions from cancer patients by Northern blotting, immunocytochemistry and in situ hybridization. Immunoreactive group II PLA2 levels were significantly higher in effusions from 47 patients with various cancers, compared with those in sera and cirrhotic ascites. There was no significant correlation between group II PLA2 levels in effusions and those in sera. Group II PLA2 mRNA was expressed at a high level in cells from effusions, by Northern blot analysis, but not in those cells from blood. The localization of group II PLA2 protein and mRNA was intense in carcinoma cells and CD68-positive macrophages, determined by immunocytochemistry and in situ hybridization. In addition, IL-6 and IL-8 levels were significantly higher in effusions, in comparison with those in sera from patients, suggesting that cancer cells and macrophages produce group II PLA2 by IL-6. These group II PLA2 levels are apparently significantly increased in effusions, and the carcinoma cells and macrophages produce group II PLA2, as noted in effusions from patients with various cancers. Int. J. Cancer 74:245-250, 1997. © 1997 Wiley-Liss, Inc.

Group II phospholipase A2 is increased in peritoneal and pleural effusions in patients with various types of cancer.

Background. Recently, the authors reported that membrane-associated phospholipase A2 (M-PLA2) was one of the acute phase reactants and increased in serum of patients with various malignant tumors.



Methods. M-PLA2 concentrations in tissue specimens from 78 breast cancers, 16 benign breast tumors, and 10 normal breast tissues were determined by a specific radioimmunoassay recently developed. Immunohistochemical staining was performed on all specimens by the avidin-biotin-peroxidase method.



Results. Tissue levels of M-PLA2 concentration were significantly higher in breast cancer than in benign breast tumor or normal breast tissue (P < 0.01). Correlation analyses between the tissue concentration of M-PLA2 and clinicopathologic factors showed that tissue M-PLA2 levels were significantly higher in patients with skin or muscle invasion, vessel involvement, and distant metastasis than in those without. In addition, this enzyme concentration was significantly greater in scirrhous carcinoma than in papillotubular or solid-tubular carcinoma. No association was found between M-PLA2 concentration and steroid hormone receptor status. Immunohistochemically, M-PLA2 was preferentially stained in the invading zone of breast cancer tissues, especially in scirrhous carcinoma. Patients with breast cancer with low levels of M-PLA2 showed significantly longer overall survival and disease-free survival compared with those with high levels of this enzyme at the cutoff point of 50 ng/100 mg protein. The combination of estrogen receptor status with M-PLA2 concentration could be a powerful prognostic factor in predicting such survival rates.



Conclusions. M-PLA2 is closely related to the malignant potential of breast cancers, and the M-PLA2 contents in breast cancer tissues could be a new valuable prognostic factor, other than the hormone receptor, in delineating the status of human breast cancer.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819930515%2971%3A10%3C3058%3A%3AAID-CNCR2820711028%3E3.0.CO%3B2-8

Increased expression of membrane-associated phospholipase A2 shows malignant potential of human breast cancer cells

We examined 55 patients (40 male, 15 female) who were diagnosed from 1987 to 1991 as having early gastric cancer (EGC) stage I according to the general rules of classification of the Japanese Research Society for Gastric Cancer. Of the 55 patients, 42 (30 male, 12 female) were alive in April 1992. The prognosis correlated well with the ratio of neutrophils to lymphocytes (N/L ratio) but not with the total number of white blood cells in the peripheral blood. The patients were divided into two groups according to their N/L ratio. Of the 29 patients with an N/L ratio less than 2, 27 were alive in 1992, whereas only 15 of the 26 patients with an N/L ratio of 2 or more were alive (χ2 analysis, P = 0.0022). We further examined the phenotypes of neutrophils from 29 other patients with EGC at the time of diagnosis before surgical operation. These patients were divided into two groups: 17 patients with a low N/L ratio (less than 2) and 12 patients with a high N/L ratio (2 or more). CD10 and CD35 expressions on neutrophils from the patients with a low N/L ratio were lower than those from the patients with a high N/L ratio. The N/L ratio correlated well with both CD10 and CD35 expression, whereas no correlation was observed between the numbers of neutrophils and the expression of these phenotypes. The respiratory burst of neutrophils from the patients with a high N/L ratio was higher than that of neutrophils from the patients with a low N/L ratio, though there was no correlation in the phagocytic activity between both groups. It was thus suggested that the heterogeneity of neutrophils is, at least partly, related to the prognosis of patients with EGC.

Kiyoshi Sakamoto

Papers

Elevation of Circulating Interleukin 6 After Surgery: Factors Influencing the Serum Level

Inhibition of stress-induced gastric injury in the rat by glutathione.

Group II phospholipase A2 is increased in peritoneal and pleural effusions in patients with various types of cancer.

Increased expression of membrane-associated phospholipase A2 shows malignant potential of human breast cancer cells

The ratio of neutrophils to lymphocytes and the phenotypes of neutrophils in patients with early gastric cancer