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 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.
Nakashima
T
T
Drug Discovery Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Miura
M
M
Hara
M
M
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D019253:Proto-Oncogene Proteins c-bcl-2; C025518:tetrocarcin A