Tetrocarcin A inhibits mitochondrial functions of Bcl-2 and suppresses its anti-apoptotic activity

Bcl-2 is an integral, intracellular membrane protein that prevents cells from undergoing apoptosis in response to a variety of cell death signals. It negatively regulates the activation of Caspase-3, which functions as effector of mammalian cell death pathways. Overexpression of Bcl-2 inhibits the c...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2000-03, Vol.60 (5), p.1229-1235
Main Authors: NAKASHIMA, T, MIURA, M, HARA, M
Format: Article
Language:English
Subjects:
Ageing, cell death
Aminoglycosides
Anti-Bacterial Agents - pharmacology
Antibiotics, Antineoplastic - pharmacology
Antineoplastic agents
Apoptosis - drug effects
Apoptosis - genetics
Biological and medical sciences
Cell physiology
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Neoplastic - drug effects
General aspects
Genes, bcl-2
HeLa Cells
Humans
Medical sciences
Mitochondria - genetics
Mitochondria - metabolism
Molecular and cellular biology
Pharmacology. Drug treatments
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Transfection
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Summary:Bcl-2 is an integral, intracellular membrane protein that prevents cells from undergoing apoptosis in response to a variety of cell death signals. It negatively regulates the activation of Caspase-3, which functions as effector of mammalian cell death pathways. Overexpression of Bcl-2 inhibits the caspase activities and apoptosis. A microbial secondary metabolite, Tetrocarcin A (TC-A), was identified as an inhibitor of the anti-apoptotic function of Bcl-2. Apoptosis could be induced in cell lines that overexpressed Bcl-2 or Bcl-XL when the cells were treated with anti-Fas antibody, tumor necrosis factor alpha, staurosporine, or Bax, in addition to TC-A. TC-A showed selectivity against the pro-apoptotic Bcl-2 family members, in that cells overexpressing CrmA or dominant-negative FADD could not undergo apoptosis with TC-A treatment. In Bcl-2-overexpressing cell lines, TC-A inhibited mitochondrial functions regulated by Bcl-2, resulting in Fas-triggered mitochondrial transmembrane potential loss and cytochrome c release. Inhibition of the mitochondrial functions of Bcl-2 and, thereby, its anti-apoptotic effect could serve as useful pharmacological targets. Thus, TC-A should serve as an archetype for specific inhibitors of Bcl-2 functions.
ISSN:0008-5472
1538-7445