PubMed · 10787708
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L J Johnson. 1999-11-22. The devastation caused by a decimal point.. https://pubmed.ncbi.nlm.nih.gov/10787708/
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Matrix Gla protein (MGP) is a vitamin K-dependent extracellular matrix protein commonly found in a variety of tissues. In this study, we describe the potential use of MGP gene expression as the tumor marker of colorectal cancer. A decrease in expression of the MGP gene was also discovered in colorectal cancer using differential screening of cDNA libraries. The MGP expression in 80 human colorectal adenocarcinomas was quantified by a Northern blot analysis to better define the expression pattern of MGP in colorectal cancer. The expression of MGP mRNA was reduced in 63 of 80 (79%) colorectal adenocarcinomas (P<0.001) as compared to the mRNA in adjacent normal tissue, implying that a decrease in MGP expression is associated with colorectal cancer development. The proportion of tumors with downregulated expression of MGP was lower in Duke's A/B than Duke's C/D (34 of 47 versus 26 of 33, respectively) tumors and was lower in moderate differentiation than poor differentiation (44 of 64 versus 16 of 16, respectively). However, chi(2) analysis does not reveal any correlation between a loss of MGP expression and tumor progression or differentiation state. In conclusion, the downregulation of MGP mRNA generally occurs in colorectal adenocarcinomas. Although the role of MGP in cancer development is unknown, the reduced expression of MGP may be used to distinguish the normal colorectal cells from malignant cells.
Clinical and laboratory studies have provided evidence of oncostatic activity by the pineal neurohormone melatonin. However, these studies have not elucidated its mechanism of action. The following series of MCF-7 breast tumor cell studies conducted in the absence of exogenous steroid hormones provide evidence for a novel mechanism of oncostatic activity by this endogenous hormone. We observed a 40--60% loss of MCF-7 cells after 20-h treatment with 100 nM melatonin, which confirmed and extended previous reports of its oncostatic potency. Interestingly, there were no observed changes in tritiated thymidine uptake, suggesting a lack of effect on cell cycle/nascent DNA synthesis. Further evidence of a cytocidal effect came from morphologic observations of acute cell death and autophagocytosis accompanied by degenerative changes in mitochondria. Studies of mitochondrial function via standard polarography revealed a significant increase in oxygen consumption in melatonin-treated MCF-7 cells. Enzyme-substrate studies of electron transport chain (complex IV) activity in detergent permeabilized cells demonstrated a concomitant 53% increase (p < 0.01) in cytochrome c oxidase activity. Additional studies of succinate dehydrogenase activity (complex II) as determined by reduction of (3-4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide demonstrated a significant increase (p < 0.05) in melatonin-treated cells and further confirmed the accelerated ET activity. Finally, there was a 64% decrease (p < 0.05) in cellular ATP levels in melatonin-treated cells. The G-protein-coupled melatonin receptor antagonist luzindole abrogated the cytotoxic and mitochondrial effects. These studies suggest a receptor-modulated pathway of cytotoxicity in melatonin-treated MCF-7 tumor cells with apparent uncoupling of oxidative phosphorylation.
PURPOSE: The radiosensitizing effect of wortmannin on human tumor cells in a low-pH microenvironment was compared with that in a neutral-pH environment. METHODS AND MATERIALS: A172 human glioblastoma cells, A549 human lung adenocarcinoma cells, and HMV-1 human melanoma cells were treated with 20 microM wortmannin 2 h before irradiation, and cell survival was examined. A low-pH microenvironment was simulated by exposing cells to low-pH culture medium for 24 h before wortmannin treatment. The effects of wortmannin on the repair of DNA double-strand breaks (dsbs) after 50-Gy irradiation in both low- and neutral-pH conditions were measured by pulsed-field gel electrophoresis. Expression of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in low-pH conditions was also compared with that in neutral-pH conditions by Western blot analysis. RESULTS: The radiosensitizing effect of wortmannin was greater in low-pH cultures than in neutral-pH cultures for all cell lines. The fast-rejoining component of DNA dsb repair was inhibited more strongly in low-pH than in neutral-pH conditions, although there was little difference in DNA-PKcs expression between groups. CONCLUSIONS: The low-pH culture condition, which was designed to mimic the microenvironment of the central tumor mass in actively proliferating solid tumors, enhanced the radiosensitizing effect of wortmannin by inhibiting the fast-rejoining component of DNA dsb repair and by prolonging the retention of nonrejoined DNA dsbs.