| alpha-fetoprotein causes apoptosis in tumor cells via a pathway independent of CD95, TNFR1 and TNFR2 through activation of caspase-3-like proteases. | |
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MedLine Citation:
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PMID: 10583368 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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alpha-Fetoprotein (AFP) is an oncoembryonal protein with multiple cell growth regulating, differentiating and immunosuppressive activities. Previous studies have shown that treatment of tumor cells in vitro with 1-10 microM AFP produces significant suppression of tumor cell growth by inducing dose-dependent cytotoxicity, but the molecular mechanisms underlying these AFP functions are obscure. Here, we show that AFP cytotoxicity is closely related to apoptosis, as shown by cell morphology, nuclear DNA fragmentation and caspase-3-like activity resulting in cleavage of poly(ADP-ribose) polymerase. Apoptosis was significantly inhibited by a CPP32 family protease inhibitor whereas a general caspase inhibitor had no inhibitory effect, showing some enhancement of AFP-mediated cell death. Using fluorogenic caspase substrates, we found that caspase-3-like proteases were activated as early as 4 h after treatment of Raji cells with 15 microM AFP, whereas caspase-1, caspase-8, and caspase-9-like activity was not detected during the time interval 0.5-17 h. AFP treatment of Raji cells increased Bcl-2 protein, showing that AFP-induced apoptosis is not explained by downregulation of the Bcl-2 gene. This also suggests that AFP operates downstream of the Bcl-2-sensitive step. AFP notably decreased basal levels of soluble and membrane-bound Fas ligand. Incubation of AFP-sensitive tumor cells (HepG2, Raji) with neutralizing anti-Fas, anti-tumor necrosis factor receptor (TNFR)1 or anti-TNFR2 mAb did not prevent AFP-induced apoptosis, demonstrating its independence of Fas-dependent and TNFR-dependent signaling. In addition, it was found that cells resistant to TNF-induced (Raji) or Fas-induced (MCF-7) apoptosis are, nevertheless, sensitive to AFP-mediated cell death. In contrast, cells sensitive to Fas-mediated cell death (Jurkat) are completely resistant to AFP. Taken as a whole, our data demonstrate that: (a) AFP induces apoptosis in tumor cells independently of Fas/Fas ligand or TNFR/TNF signaling pathways, and (b) AFP-mediated cell death involves activation of the effector caspase-3-like proteases, but is independent of upstream activation of the initiator caspase-1, caspase-8, and caspase-9-like proteases. |
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Authors:
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E Dudich; L Semenkova; I Dudich; E Gorbatova; N Tochtamisheva; E Tatulov; M Nikolaeva; G Sukhikh |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: European journal of biochemistry / FEBS Volume: 266 ISSN: 0014-2956 ISO Abbreviation: Eur. J. Biochem. Publication Date: 1999 Dec |
Date Detail:
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Created Date: 2000-01-31 Completed Date: 2000-01-31 Revised Date: 2007-07-23 |
Medline Journal Info:
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Nlm Unique ID: 0107600 Medline TA: Eur J Biochem Country: GERMANY |
Other Details:
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Languages: eng Pagination: 750-61 Citation Subset: IM |
Affiliation:
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Institute of Engineering Immunology, Lyubuchany, Moscow Region, Russia. dudich@ineos.ac.ru |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, CD
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metabolism Antigens, CD95 / metabolism Apoptosis / drug effects*, immunology, physiology* Caspase 3 Caspases / metabolism* DNA Fragmentation / drug effects Enzyme Activation / drug effects Fas Ligand Protein Membrane Glycoproteins / metabolism Poly(ADP-ribose) Polymerases / metabolism Proto-Oncogene Proteins c-bcl-2 / metabolism Receptors, Tumor Necrosis Factor / metabolism Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Tumor Cells, Cultured Tumor Necrosis Factor-alpha / pharmacology alpha-Fetoproteins / pharmacology*, physiology |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD; 0/Antigens, CD95; 0/Fas Ligand Protein; 0/Membrane Glycoproteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptors, Tumor Necrosis Factor; 0/Receptors, Tumor Necrosis Factor, Type I; 0/Receptors, Tumor Necrosis Factor, Type II; 0/Tumor Necrosis Factor-alpha; 0/alpha-Fetoproteins; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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