Inhibition of lysosome degradation on autophagosome formation and responses to GMI, an immunomodulatory protein from Ganoderma microsporum.
Summary of "Inhibition of lysosome degradation on autophagosome formation and responses to GMI, an immunomodulatory protein from Ganoderma microsporum."
Background and purpose: Autophagic cell death is considered a self-destructive process that results from large amounts of autophagic flux. In our previous study, GMI, a recombinant fungal immunomodulatory protein cloned from Ganoderma microsporum, induced autophagic cell death in lung cancer cells. The aim of this study is to examine the role of autophagosome accumulation in GMI-mediated cell death. Experimental approach In vitro assay was performed on Western blot, flow cytometer and confocal microscope from parental and short hairpin RNAi to ATP6V0A1 cancer cells to evaluate the effect in lung cancer cell viability. Key results Lysosome inhibitors bafilomycin-A1 and chloroquine increased GMI-mediated autophagic cell death. GMI and bafilomycin-A1 co-treatment induced accumulation of large amounts of autophagosomes, but did not significantly induce apoptosis. GMI elicits autophagy through Akt/mTOR signaling pathway. Silencing of ATP6V0A1, one subunit of vesicular H(+) -ATPases (V-ATPases) which mediates lysosome acidification, spontaneously induced autophagosome accumulation, but did not affect lysosome acidity. GMI-mediated autophagosome accumulation and cytotoxicity increased in shATP6V0A1 lung cancer cells. Further, ATP6V0A1 silencing decreased autophagosome and lysosome fusion in GMI-treated CaLu-1/GFP-LC3 lung cancer cells. Conclusion and Implications In this study, we demonstrated that autophagosome accumulation induces autophagic cell death in GMI treatment model and ATP6V0A1 plays an important role in mediating autophagosome-lysosome fusion. Our findings provide new insight into autophagic cell death induction mechanisms. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Affiliation
Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan Division of Allergy, Department of Pediatrics, Chung Shan Medical University Hospital, Ta
Journal Details
This article was published in the following journal.
Name: British journal of pharmacology
ISSN: 1476-5381
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22708544
- DOI: http://dx.doi.org/10.1111/j.1476-5381.2012.02073.x
Medical and Biotech [MESH] Definitions
Lysosome-associated Membrane Glycoproteins
Ubiquitously expressed integral membrane glycoproteins found in the LYSOSOME.
Cytochalasin D
A fungal metabolite that blocks cytoplasmic cleavage by blocking formation of contractile microfilament structures resulting in multinucleated cell formation, reversible inhibition of cell movement, and the induction of cellular extrusion. Additional reported effects include the inhibition of actin polymerization, DNA synthesis, sperm motility, glucose transport, thyroid secretion, and growth hormone release.
Lysosomes
A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured. Such rupture is supposed to be under metabolic (hormonal) control. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)
Bone Morphogenetic Protein 5
A bone morphogenetic protein that may play a role in CARTILAGE formation. It is a potent regulator of the growth of CHONDROCYTES and the synthesis of cartilage matrix proteins. Evidence for its role in cartilage formation can be seen in MICE, where genetic mutations that cause loss of bone morphogenetic protein 5 function result in the formation of small malformed ears.
Reactive Inhibition
Tendency toward a lessened strength of response due to practice or activity. It is independent of the effect of reward and is a direct function of time interval since the last response and the number of preceding responses.
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