Autophagy in tumour cell death Macintosh, Robin L; Ryan, Kevin M
Seminars in cancer biology,
10/2013, Letnik:
23, Številka:
5
Journal Article
Recenzirano
Abstract In every moment of a cell's existence one key question is always asked, “To be or not to be”? Cells constantly weigh up signals from their environment against their own integrity and ...metabolic status and decide whether to live or die. Such cell death decisions are central to the progression and treatment of cancer. The term autophagy describes three processes that deliver cytoplasmic macromolecules and organelles to lysosomes for degradation, the difference between each form being the method of delivery. The most extensively studied form is macroautophagy (hereafter referred to as autophagy) where cytosolic components are engulfed by double membraned autophagosomes. Autophagosomes fuse with lysosomes to form structures called autolysosomes, within which organelles, proteins and other macromolecules are degraded by catabolic enzymes in the acidic lysosome environment. Autophagy, which normally occurs at low levels in unstressed cells, is widely regarded as having a positive effect on cell health as potentially harmful protein aggregates and damaged organelles can be recycled. During periods of nutrient shortage autophagy is enhanced to provide, albeit temporarily, an internal energy source. Autophagy is also enhanced by other stresses encountered by tumour cells and this may protect the cell or aid its demise. In this review we examine the effect of autophagy on cell death decisions in tumour cells.
Autophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. It contributes to energy and organelle homeostasis and the preservation of proteome ...and genome integrity. Although a role in cancer is unquestionable, there are conflicting reports that autophagy can be both oncogenic and tumor suppressive, perhaps indicating that autophagy has different roles at different stages of tumor development. In this report, we address the role of autophagy in a critical stage of cancer progression-tumor cell invasion. Using a glioma cell line containing an inducible shRNA that targets the essential autophagy gene Atg12, we show that autophagy inhibition does not affect cell viability, proliferation or migration but significantly reduces cellular invasion in a 3D organotypic model. These data indicate that autophagy may play a critical role in the benign to malignant transition that is also central to the initiation of metastasis.
S. epidermidis is one of the primary opportunistic pathogens associated withindwelling medical devices such as intravenous catheters and artificial heartvalves and joints. S. epidermidis is also a ...permanent commensal resident onhuman skin and mucus membranes providing a large potential reservoir for thecontamination of medical implants. Persistent colonisation of implants occurs viabiofilm formation and infected implants must usually be replaced. The surfaceboundprotein, accumulation associated protein (Aap), is one of the main biofilmpromoting surface molecules on S. epidermidis. Aap is a LPXTG protein with arepetitive B-region, thought to promote biofilm formation as well as providing astalk structure to project the A-domain away from the cell surface. Aap isexpressed in lateral tufts of fibrils on the surface of a sub-population of strainNCTC 11047 and, here, similar sub-populations are shown to be present inother S. epidermidis strains. In order to determine the function of specificdomains of Aap in adhesion and biofilm formation Aap constructs with andwithout the A-domain and with varying numbers of B-repeats were expressed onthe surface of Lactococcus lactis MG1363 and Staphylococcus aureus. Theexpression of Aap with the A-domain on the surface of L. lactis increasedcorneocyte adhesion 20-fold compared to L. lactis carrying Aap without an Adomain. Several S. epidermidis isolates also used the A-domain of Aap toadhere to corneocytes, emphasizing the role of Aap in skin adhesion. Inaddition, Aap promoted adhesion to polystyrene although only the A-domainadditionally promoted adhesion to tissue culture treated polystyrene.Furthermore, biofilms were cultivated under flow conditions and analyzed byconfocal microscopy. Aap, with the A-domain on the surface of both L. lactis andS. aureus, enhanced microcolony formation suggesting a potential role for the Adomainin the early stage of biofilm formation. The A-domain of Aap is thereforemultifunctional because, in addition to mediating adhesion to corneocytes it canpromote initial attachment to polystyrene and functions in the early accumulationstage of biofilm formation.
One component of the safety assessment of agricultural products produced through biotechnology is evaluation of the safety of newly expressed proteins. The ILSI International Food Biotechnology ...Committee has developed a scientifically based two-tiered, weight-of-evidence strategy to assess the safety of novel proteins used in the context of agricultural biotechnology. Recommendations draw upon knowledge of the biological and chemical characteristics of proteins and testing methods for evaluating potential intrinsic hazards of chemicals. Tier I (potential hazard identification) includes an assessment of the biological function or mode of action and intended application of the protein, history of safe use, comparison of the amino acid sequence of the protein to other proteins, as well as the biochemical and physico-chemical properties of the proteins. Studies outlined in Tier II (hazard characterization) are conducted when the results from Tier I are not sufficient to allow a determination of safety (reasonable certainty of no harm) on a case-by-case basis. These studies may include acute and repeated dose toxicology studies and hypothesis-based testing. The application of these guidelines is presented using examples of transgenic proteins applied for agricultural input and output traits in genetically modified crops along with recommendations for future research considerations related to protein safety assessment.
The vesicular monoamine transporter 2 (VMAT2) sequesters monoamines into synaptic vesicles in preparation for neurotransmission. Samples of cerebellum, cortex, hippocampus, substantia nigra and ...striatum from VMAT2-deficient mice were compared to age-matched control mice. Multivariate statistical analyses of
1
H NMR spectral profiles separated VMAT2-deficient mice from controls for all five brain regions. Although the data show that metabolic alterations are region- and age-specific, in general, analyses indicated decreases in the concentrations of taurine and creatine/phosphocreatine and increases in glutamate and
N
-acetyl aspartate in VMAT2-deficient mouse brain tissues. This study demonstrates the efficacy of metabolomics as a functional genomics phenotyping tool for mouse models of neurological disorders, and indicates that mild reductions in the expression of VMAT2 affect normal brain metabolism.
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