Several types of cancer cells, including colorectal cancerderived cell lines, show austerity, the resistance to nutrient starvation, but exactly how cancer cells obtain energy sources under conditions in which their external nutrient supply is extremely limited remains to be clarified. Because autophagy is a catabolic process by which cells supply amino acids from self-digested organelles, cancer cells are likely to use autophagy to obtain amino acids as alternative energy sources. Amino acid deprivation-induced autophagy was assessed in DLD-1 and other colorectal cancer-derived cell lines. The autophagosome-incorporated LC3-II protein level increased after treatment with a combination of autolysosome inhibitors, which interferes with the consumption of autophagosomes. Autophagosome formation was also morphologically confirmed using ectopically expressed green fluorescent protein-LC3 fusion proteins in DLD-1 and SW480 cells. These data suggest that autophagosomes were actively produced and promptly consumed in colorectal cancer cells under nutrient starvation. Autolysosome inhibitors and 3-methyl adenine, which suppresses autophagosome formation, remarkably enhanced apoptosis under amino acid-deprived and glucosedeprived condition. Similar results were obtained in the cells with decreased ATG7 level by the RNA interference. These data suggest that autophagy is pivotal for the survival of colorectal cancer cells that have acquired austerity. Furthermore, autophagosome formation was seen only in the tumor cells but not in the adjacent noncancerous epithelial cells of colorectal cancer specimens. Taken together, autophagy is activated in colorectal cancers in vitro and in vivo, and autophagy may contribute to the survival of the cancer cells in their microenvironment. [Cancer Res 2007;67(20):9677-84]
Upon activation of cell surface receptors coupled to the Gq subclass of G proteins, phospholipase C (PLC) beta hydrolyses membrane phospholipid to yield a pair of second messengers, inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol. PLCbeta4 has been characterized as the isoform enriched in cerebellar Purkinje cells (PCs) and the retina and involved in motor and visual functions. Here we examined cellular and subcellular distributions of PLCbeta4 in adult mouse brains. Immunohistochemistry showed that high levels of PLCbeta4 were detected in the somatodendritic domain of neuronal populations expressing the metabotropic glutamate receptor (mGluR) type 1alpha, including olfactory periglomerular cells, neurons in the bed nucleus anterior commissure, thalamus, substantia nigra, inferior olive, and unipolar brush cells and PCs in the cerebellum. Low to moderate levels were detected in many other mGluR1alpha-positive neurons and in a few mGluR1alpha-negative neurons. In PCs, immunogold electron microscopy localized PLCbeta4 to the perisynapse, at which mGluR1alpha is concentrated, and to the smooth endoplasmic reticulum in dendrites and spines, an intracellular Ca2+ store gated by IP3 receptors. In the cerebellum, immunoblot demonstrated its concentrated distribution in the post-synaptic density and microsomal fractions, where mGluR1alpha and type 1 IP3 receptor were also greatly enriched. Furthermore, PLCbeta4 formed coimmunoprecipitable complexes with mGluR1alpha, type 1 IP3 receptor and Homer 1. These results suggest that PLCbeta4 is preferentially localized in the perisynapse and smooth endoplasmic reticulum as a component of the physically linked phosphoinositide signaling complex. This close molecular relationship might provide PLCbeta4 with a high-fidelity effector function to mediate various neuronal responses under physiological and pathophysiological conditions.
Ligand binding to neurotransmitter and hormone receptors which couple to the Gq subclass of GTP-binding protein leads to the activation of phospholipase Cbeta (PLCbeta) which hydrolyses phosphatidyl-inositol 4,5-bisphosphate, yielding a pair of second messengers, diacylglycerol and inositol 1,4,5-trisphosphate (IP3). The expression of PLCbeta1-4 mRNAs was comparatively examined by in situ hybridization in the mouse brain. In adults, PLCbeta1 mRNA was expressed predominantly in the telencephalon, including the cerebral cortex, hippocampus, amygdala, lateral septum and olfactory bulb, with little expression in most thalamic nuclei. PLCbeta2 mRNA was distributed in the white matter, suggesting its expression in non-neuronal cells, most likely oligodendrocytes. PLCbeta3 mRNA was specifically expressed in cerebellar Purkinje cells. The highest levels of PLCbeta4 mRNA were detected in Purkinje cells. High levels of PLCbeta4 mRNA were also found in the thalamus and medial septum, whereas weak signals were detected in most telencephalic regions, thus showing an expression pattern almost reciprocal to that of PLCbeta1 mRNA. During development, such characteristic regional expression of PLCbeta1 and PLCbeta4 were observed starting in late foetal stages, while specific expression of PLCbeta2 and PLCbeta3 appeared in early postnatal stages. We conclude that despite the existence of four PLCbeta isoforms, only one or two of them is expressed in individual neurons and glial cells. The distinct expression of PLCbetas provides a molecular basis for analysing the nature of the specific signal transduction pathway leading to the production of diacylglycerol and IP3 in distinct cell types and in different regions of the brain.
ABSTRACT-Although improving energy metabolism in ischemic brain has been accepted for the treatment of cerebrovascular diseases, administration of glucose, as an energy substrate, would aggravate ischemic brain damage via activating anaerobic glycolysis, which leads to lactate accumulation. b-hydroxybutyrate (BHB) is one of the ketone bodies that can be utilized as an energy source during starvation. The purpose of our study was to define the protective effects of BHB on brain damage induced by hypoxia, anoxia and ischemia. The isotonic solution of BHB administered 30 min before the induction of ischemia at doses over 50 mg · kg -1 ·h -1 showed remarkable protective effects against hypoxia and anoxia. BHB administered immediately after a bilateral carotid artery ligation at a dose of 30 mg·kg -1 ·h -1 significantly suppressed the elevation of cerebral water and sodium contents as well as maintaining high ATP and low lactate levels. In contrast, glycerin, a hypertonic agent, substantially reduced the water content but did not show any significant effect on other parameters. We demonstrated that BHB, unlike glycerin, when used as an energy substrate in ischemic brain, has protective effects on cerebral hypoxia, anoxia and ischemia-induced metabolic change.Keywords: b -Hydroxybutyrate, Glycerin, Anti-anoxic effect, Cerebral ischemia, Cerebral energy metabolism The brain is a surprisingly active tissue in terms of glucose metabolism; almost all the energy supplied to maintain its vital functions are derived from glucose oxidation. Restriction of the glucose supply and metabolism under such conditions as hypoxia and ischemia would result in brain damages (cerebral edema and infarct). However, epidemiological data have shown that hyperglycemia was associated with higher risks of strokes and that ischemic cerebral injury was, at least partly, attributed to hyperglycemia as well (1 -3). Furthermore, it has been verified in several animal models that glucose administration accelerated brain damage caused by cerebral ischemia (4 -6). The elevated glucose anaerobic metabolism under hypoxia and ischemia conditions (6 -9) causes tissue lactate accumulation which subsequently leads to an increased H + intracellular concentration level. It is thus conclusive to state that glucose containing solutions have or might have harmful effects in an ischemic brain.Ketone bodies are known for their energy source uses in states of starvation (10). b-Hydroxybutyrate (BHB, Fig. 1), a representative type of ketone body, is produced by degradation of fatty acids in the liver. Recent studies have reported the utilization of BHB as an energy substrate in head trauma patients (11) and hemorrhage shock rats (12). Go et al. reported that fasting, characterized by features like hypoglycemia and ketosis, protected rats from developing brain infarction following hypoxia-ischemia (13). The rats were found to have an increased level of BHB in their blood compared with rats that had a normal *Corresponding author. FAX: +81-543-35-4858 E-mail: motohisa-...
Curability and anal function were achieved by means of intersphincteric resection without or with additional partial external sphincteric resection. These procedures can be recommended for low rectal cancer patients who are candidates for abdominoperineal resection.
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